Download View Full Page PDF

PHYSIOLOGICAL REVIEWS
Vol. 81, No. 4, October 2001
Printed in U.S.A.
Architecture of the Optic Chiasm
and the Mechanisms That Sculpt Its Development
GLEN JEFFERY
University College London, Institute of Ophthalmology, London, United Kingdom
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
I. Introduction
II. The Mature Structure of the Mammalian Chiasm
A. Chiasmatic pathways and the naso-temporal division in the retina
B. Patterns of fiber order in the optic nerve
C. Wilbrand’s knee in the proximal optic nerve
D. Changes in fiber order between the optic nerve and optic tract
E. The course of crossed axons through the chiasmatic region
F. The course of uncrossed axons through the chiasmatic region
III. Development of the Mammalian Chiasm
A. Potential mechanisms for chiasm generation
B. Ganglion cell generation and optic chiasm formation
C. Axon extension and morphological development of retinal axons
D. Adhesion molecules and pathway markers
E. Genetic regulation of chiasm development
F. Role of chiasmatic neurons in chiasm pathway selection
G. Role of chiasmatic glia in chiasm pathway selection
H. Interactions between fibers from each eye at the developing chiasm
IV. Chiasmatic Abnormalities Found in Albinism
A. Role of temporal ordering in patterns of retinal cell addition and outgrowth
V. Mature Structure and Development in Nonmammalian Vertebrates
A. Amphibians
B. Birds
VI. Conclusion
1393
1394
1394
1395
1396
1396
1396
1398
1399
1399
1399
1401
1403
1404
1405
1406
1407
1408
1408
1409
1409
1410
1410
Jeffery, Glen. Architecture of the Optic Chiasm and the Mechanisms That Sculpt Its Development. Physiol Rev 81:
1393–1414, 2001.—At the optic chiasm the two optic nerves fuse, and fibers from each eye cross the midline or turn back
and remain uncrossed. Having adopted their pathways the fibers separate to form the two optic tracts. Research into the
architecture and development of the chiasm has become an area of increasing interest. Many of its mature features are
complex and vary between different animal types. It is probable that numerous factors sculpt its development. The
separate ganglion cell classes cross the midline at different locations along the length of the chiasm, reflecting their
distinct periods of production as the chiasm develops in a caudo-rostral direction. In some mammals, uncrossed axons
are mixed with crossed axons in each hemi-chiasm, whereas in others they remain segregated. These configurations are
the product of different developmental mechanisms. The morphology of the chiasm changes significantly during
development. Neurons, glia, and the signals they produce play a role in pathway selection. In some animals fiber-fiber
interactions are also critical, but only where crossed and uncrossed pathways are mixed in each hemi-chiasm. The
importance of the temporal dimension in chiasm development is emphasized by the fact that in some animals uncrossed
ganglion cells are generated abnormally early in relation to their retinal location. Furthermore, in albinos, where many
cells do not exit the cell cycle at normal times, there are systematic chiasmatic abnormalities in ganglion cell projections.
I. INTRODUCTION
At the optic chiasm, axons of retinal ganglion cells
either cross the midline and innervate the contralateral
hemisphere or remain uncrossed and project ipsilaterally.
www.prv.org
There is renewed interest in the chiasm because the binary decision made by optic axons may cast light on
fundamental mechanisms of axon guidance in the central
nervous system (CNS). However, surprisingly little is
known about the mature organization of the chiasm, how
0031-9333/01 $15.00 Copyright © 2001 the American Physiological Society
1393
1394
GLEN JEFFERY
Physiol Rev • VOL
abnormalities of the chiasm where these cast light on
mechanisms of normal development.
II. THE MATURE STRUCTURE OF THE
MAMMALIAN CHIASM
A. Chiasmatic Pathways and the Naso-temporal
Division in the Retina
Optic decussation was first postulated by Albert the
Great, who in the 13th century noted the loss of contralateral visual fields after unilateral damage to the back of the
head (158). The partial pattern of decussation at the chiasm was first proposed by Newton (107), but was formulated more explicitly by Taylor almost 100 years later
(117, 153). Such a pattern forms the basis of binocular
vision, such that in humans, fibers originating from the
temporal retina remain uncrossed at the chiasm, whereas
those originating from the nasal retina cross. This pattern
of partial decussation results in the continuity of the
visual field representation in central visual structures in
the brain. The line that divides these two populations of
ganglion cells in the retina passes vertically through the
fovea. The projections from each eye are in conjugate
register in the lateral geniculate nucleus, which projects a
map of the visual hemifield to the primary visual cortex
(43, 85, 117).
The retinal line that segregates ipsilaterally from contralaterally projecting cells is termed the naso-temporal
division and has varying degrees of precision depending
on the species examined. In all cases the crossed projection is larger than the uncrossed. Generally, in mammals,
the majority of fibers that give rise to the uncrossed
chiasmatic pathway are located in the temporal retina,
but complete spatial segregation of cells giving rise to
crossed and uncrossed pathways is primarily the preserve
of primates (43). In most mammals other than primates,
the crossed projection arises from the entire retina,
whereas the uncrossed projection is mainly confined to
the region temporal to the area of maximum ganglion cell
density, the area centralis (29, 37, 55, 81). In these animals
the temporal retina contains a mixed population of cells
in terms of their chiasmatic pathways. The relative proportion of cells within the temporal retina that project
ipsilaterally varies with the degree of retinal specialization and the location of the eyes in the head, and hence
the size of their binocular visual field. In the cat, which
has frontally placed eyes, cells with an uncrossed pathway form a greater proportion of the total ganglion cell
population in the temporal retina than they do in rodents,
who have a less specialized retina than that commonly
found in carnivores and laterally placed eyes. Rabbits
have specialized retinae, but very laterally placed eyes,
and hence a small uncrossed pathway (29, 37, 70, 78, 118).
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
this varies between mammals, or the developmental
mechanisms that sculpt its architecture. This review focuses on the chiasm in animals with partial patterns of
decussation, where fibers from each eye give rise to both
crossed and uncrossed hemispheric pathways. In these
animals chiasmatic organization is more complex, and
from a developmental point of view probably more interesting, because each fiber is required to make a choice as
to whether it crosses the midline or not.
It is thought that optic fibers project across the midline because early in evolution they innervated motor
neurons on the contralateral side of the body in primitive
bilaterally symmetrical animals. Any change in illumination, such as the movement of a shadow, was interpreted
as indicating the potential presence of a predator. Hence,
the crossed fibers provided a simple reflexive pathway for
turning away from the potentially threatened side (136).
Although this assumes that the crossed chiasmatic pathway predates the evolution of the uncrossed projection,
ipsilaterally projecting fibers are not the preserve of mammals, but can be found, to a greater or lesser extent, in
adult members of all vertebrate classes including the
agnathans (jawless fish), amphibians, and birds (170).
Hence, it can be assumed that partial patterns of decussation have a long ancestral history.
Although there are extensive data in a range of vertebrates on the existence of crossed and uncrossed projections, few consider the organization of fibers through
the chiasm and how they develop. The literature on this
subject is marked by a limited number of detailed studies
undertaken in a few specific animal models, which with a
few exceptions are almost exclusively confined to mammals. These studies do not always tell a consistent story,
and there is growing evidence that even within mammals,
the organization of the chiasm is variable, and as such, the
factors that influence its development are probably not
universal. Despite this, considerable advances are being
made in our understanding of the mechanisms of chiasmatic pathway selection in the mouse. The advantage of
using the mouse is the relative ease with which methods
of molecular genetics can be applied to addressing the
problems of CNS development.
This review considers the fiber organization of the
chiasm and how this might arise. This cannot be undertaken without reviewing the organization of the optic
nerve and tract as well as patterns of retinal ganglion cell
production. The role of fiber-fiber interactions and fiberglia relationships in the chiasm is also reviewed. Although
there is an ever-expanding literature on chemical signals/
markers in development, these are not considered extensively, but only where they are directly relevant to the
chiasm. Likewise, the literature on differential neural adhesion chemicals are not extensively reviewed because
these appear to play a smaller role in pathway selection
than was originally thought. Consideration is given to
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
Physiol Rev • VOL
B. Patterns of Fiber Order in the Optic Nerve
Patterns of fiber order through the optic chiasm are
dependent on those in the optic nerve. Considerable debate has taken place as to whether the nerve is retinotopically organized or not. It had been proposed that in
both cat and primate fibers were not organized in a meaningful way but were relatively random (62, 69). The limitations of these studies were that they examined only a
small sample of optic fibers either anatomically or physiologically. When larger populations are considered following tracer injections into the brain, or retinal lesions,
it is clear that for the greater length of the nerve the
majority of fibers are organized in a roughly retinotopic
manner (5, 55, 68, 76, 104, 105). Occasionally fibers can be
identified that do not conform to this pattern, but they
remain in the minority and do not appear to arise from
any specific functional class (76). This pattern appears to
be present in all of the mammals studied to date. However, depending on the animal type, it can change in the
proximal optic nerve just before fibers enter the chiasm.
In rodents and carnivores, gradients in ganglion cell
density across the retina are far less marked than they are
in primates. In primates a much greater proportion of
ganglion cells arise from the central retina due to the
highly developed degree of retinal specialization in this
animal (43, 70). Consequently, fibers from this region
occupy a greater proportion of the nerve. A number of
studies have traced the course of fibers from the papillomacular region. These have shown that behind the eye
they occupy a wedge-shaped region in the temporal sector
of the nerve, but more caudally they are located in a
central core of the nerve (17, 33, 104, 117). There is some
discrepancy regarding the precise distribution of these
fibers prechiasmatically, as just before the nerves meet at
the chiasm they may be distributed more widely (67).
Although optic fibers are grouped within fascicles
from the optic nerve head into the intracranial segment, in
some animals these patterns are no longer present in
regions adjacent to the chiasm. This change from a fascicular to a nonfascicular configuration has been seen in
some primates, carnivores, rodents, and marsupials (4, 55,
76) and is associated with a change in the glial organization of the nerve at this location (52). In some animals the
change in glial organization is associated with a change in
fiber order such that the roughly retinotopic representation found along the majority of the length of the nerve is
lost in this region, and fibers destined to project to different hemispheres become completely mixed (4 – 6, 76).
These significant changes in fiber order in proximal regions have been identified in carnivores (4, 76) and rodents (5) but may be the preserve of these animals alone.
In some marsupials the fascicular organization of the
nerve is lost in regions close to the chiasm, but there is no
major change in nerve fiber order (55). Hence, the loss of
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Cells giving rise to the uncrossed projection terminate in the main visual nuclei that receive retinal input.
These include the lateral geniculate nucleus (LGN), the
superior colliculus (SC), and pretectal nuclei (171). They
also project to the superachiasmatic nucleus and the accessory optic system (183). In primates, retinal projections to both the LGN and SC respect the sharp nasotemporal division, in that only cells located nasal to the
fovea project to the contralateral LGN and SC (31, 43).
Although the projection to the LGN respects the nasotemporal division in carnivores, the projection to the SC
does not. Hence, although cells projecting ipsilaterally to
the SC are confined to the temporal retina, cells projecting to the contralateral SC are found distributed across
the entire retina (173). The only exception to this is the
projection pattern found in large fruit-eating bats, which
have a retinal projection to the SC with a vertical hemidecussation of the kind commonly only found in primates
(115). This pattern is not found in other bats and has given
rise to considerable speculation about the evolutionary
relationship between mega bats and primates (116).
In the cat, the line that segregates the uncrossed cells
projecting to the LGN varies depending on the subtypes of
ganglion cell considered. In this animal, as in most mammals, ganglion cells can be grouped roughly into three
classes on the basis of morphology and physiological
properties (15). ␤-Cells form almost half of the ganglion
cell population and have brisk sustained responses and
medium-sized cell bodies. They project primarily to the
LGN (171, 172). These cells have a relatively sharp nasotemporal division as the line segregating those with different chiasmatic routes is ⬍1° wide (89). However,
␣-cells that form a much smaller percentage of the total
population and have large cell bodies and a more transient response (172) have a much wider naso-temporal
division, with some cells still found projecting across the
midline over 15° into the temporal retina (89). These cells
project to both the LGN and the SC (171). The different
way that the separate cell types straddle the naso-temporal division in the cat appear also to be present in primates (43, 93).
The separate chiasmatic configurations of the different cell types demonstrate that the extent to which retinal
location determines chiasmatic pathways can vary with
the cell type that is being considered. This point may be of
significance when the development of these different cell
types is considered in relation to their patterns of projection.
A small population of retinal ganglion cells has been
identified in rodents and cats that have bifurcating axons
that project to both sides of the brain. It is not clear where
the axon bifurcation occurs. These cells are rare and are
confined to the temporal retina (73, 78). Cells that project
bilaterally do not appear to arise from any particular cell
type.
1395
1396
GLEN JEFFERY
fascicular organization is not necessarily associated with
a major change in fiber order. In the tree shrew, fascicular
patterns found along the length of the nerve remain in
proximal regions and are also found deep in the chiasm.
In this animal there is no change in fiber order in the
proximal nerve (81). These studies show that there are
wide variations in the organization of the proximal nerve
within mammals and that only within a limited range of
mammals does there appear to be significant changes in
fiber order in these proximal regions.
C. Wilbrand’s Knee in the Proximal Optic Nerve
D. Changes in Fiber Order Between the Optic
Nerve and Optic Tract
The roughly retinotopic pattern of organization of the
nerve as revealed by degeneration or modern tracing
methods is consistent with observations made of the distribution of axons of different sizes along the nerve. In
Physiol Rev • VOL
E. The Course of Crossed Axons Through
the Chiasmatic Region
To date there has only been one major study that has
traced the course of axons with different diameters
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
The region of the proximal nerve where the fascicular configuration is lost in some animals has been thought
to contain fibers from both eyes, as fibers from the other
eye that have crossed the midline, course through here in
a loop before turning back toward the optic tract (117).
They were thought to form the anatomical basis of the
anterior chiasmal syndrome resulting from a tumor or
compression of the proximal nerve. In this condition, not
only is there a loss of vision from the eye from which the
nerve originates, but also a superior temporal hemianopia
in the other eye (10).
Wilbrand first identified these fibers in silver-stained
sections from a human chiasm where one eye had been
lost a number of years before death (117, 176). Although
Wilbrand’s knee fibers are mentioned in many text books
and have been referred to frequently, recent research has
demonstrated that they are an artifact resulting from a
distortion in the chiasmatic region as a consequence of
long-term degeneration following eye loss. These fibers
almost certainly originate from more central regions of
the chiasm but are shifted with time into regions previously occupied by the now absent proximal nerve. With
modern tracing techniques, Wilbrand’s knee fibers cannot
be identified in the normal primate chiasm or in those
from primates after recent monocular enucleation. However, they are present after longer term survival after
monocular enucleation (61). The author of this study also
points out that as these fibers were thought to extend only
⬃2 mm down the contralateral nerve, it was most unlikely
that any tumor would compress this region without involvement of the main body of the chiasm itself. Hence,
even the clinical evidence in favor of the existence of
these fibers was not compelling.
general, mammalian optic fibers can be classified on the
basis of size into three groups reflecting the three main
types of retinal ganglion cell (171, 179). The majority of
these are either medium or fine, but a smaller proportion
is coarse. This trimodal distribution of fiber sizes reflects
the size differences in the main types of ganglion cell (15).
In the primate, cat, and rodent there is no obvious rearrangement of fibers based on size along the length of the
nerve. Fiber distribution reflects that of their parent cell
bodies in the retina, as all three types can be found at all
locations across the nerve (122, 128, 179). This is in
marked contrast to their distribution in the optic tract.
Here fibers are partially segregated on the basis of their
size. The large fibers are grouped superficially, the medium-caliber fibers are located deepest, and the fine fibers
are most common close to the pial surface (51, 122, 127).
Although there is a partial segregation of axons by
size within the tract, it would be an oversimplification to
say that this represents a change from a retinotopic to a
nonretinotopic fiber distribution. Although the axon
groups have become reordered, each group is roughly
organized in an independent retinotopic pattern. This results in the dorsoventral retinal axis being represented
across the mediolateral dimension in the optic tract and
the center to periphery axis being represented across the
depth of the tract. However, the precision of this representation is relatively poor (127, 159).
The observation that there are major differences in
the organization of the three fiber classes between the
nerve and the tract reveals that optic fibers not only
segregate depending on whether they cross the midline or
not. Within the chiasmatic region they also change their
relative order before entering the optic tract. Hence, the
chiasm is a region in which there are major changes in
fiber order.
Although the analysis of the relative locations of
optic nerve fibers of different size has been important in
revealing the organization of retinal pathways, a qualification needs to be taken into account when considering
studies that have relied on such methods. Baker and
Stryker (7) demonstrated anatomically and physiologically in the ferret that optic axon size is not fixed, but that
there is an increase in axon size between the nerve and
tract. However, there are no grounds for assuming that
different axon groups change their relative size. Rather,
there are reasons for believing that all fibers increase in
size along the length of the optic pathway because their
fiber spectrum is trimodal in both the nerve and tract.
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
including those in the far temporal periphery, have
crossed chiasmatic pathways (162).
Despite these qualifications, the data provided by
Reese and Baker (123) represent an important advance in
our understanding of chiasmatic organization, as they
have demonstrated that fibers of the three main ganglion
cell types, as determined by axon diameters, cross the
midline at different locations along the length of the chiasm (Fig. 1). The coarse fibers, all of which project across
the midline, cross rostrally in the chiasm and move to
take up a superficial location in the tract. Fine fibers that
cross the midline do so at a relatively rostral location,
from which they move to adopt a superficial position in
the optic tract. Medium-sized fibers that project across
the midline do so caudally and pass into deep regions of
the tract.
Although it is possible to divide the midline axis
according to where axons from specific classes decussate, it is also possible to divide the chiasm across the
FIG. 1. The course of fibers with different diameters through the ferret chiasm. Fibers with different diameters are
mixed along most of the length of the nerve (1). Just in front of the chiasm the majority of medium-diameter fibers
segregate into the dorsal part of the nerve, leaving the ventral part of the nerve occupied by coarse and fine fibers (2).
As soon as the nerves fuse, the coarse fibers cross the midline in the rostral chiasm along with many of the fine fibers
(3). At mid-chiasmal regions, most of the decussating fine and coarse fibers have crossed the midline, while the majority
of medium fibers have yet to do so (4). Further caudally, medium fibers either decussate or enter the ipsilateral optic
tract (5). At the caudal-most region of the chiasm, the fiber order found in the optic tract is established (6). ON, optic
nerve; OX, optic chiasm; OT, optic tract. [From Reese and Baker (123). Copyright Blackwell Science Ltd.]
Physiol Rev • VOL
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
through the mammalian chiasm to reveal the pathway
taken by different ganglion cell types, and this has been
undertaken in the ferret (123). It is important to note that
although this animal is an established model, it differs in
two important aspects from other animals studied. First,
axons with different sizes begin to segregate in the most
proximal region of the nerve, while in other mammals this
appears to occur in the chiasm (4). Hence, proximally,
coarse and fine fibers become increasingly confined to
ventral regions of the nerve leaving the dorsal region
occupied predominantly by intermediate-caliber fibers. It
is not clear why the ferret initiates the segregation of
axons here, but currently there is no reason to believe
that this reflects a major difference in chiasm organization
in this animal compared with others. Second, in the cat,
rodent, and primate, ganglion cells from each of the three
main cell types contribute components to the uncrossed
chiasmatic pathway (43, 126, 171). Unusually, all of the
cells with large axons that arise from ␣-cells in the ferret,
1397
1398
GLEN JEFFERY
F. The Course of Uncrossed Axons Through
the Chiasmatic Region
In the proximal nerve close to the chiasm, the fascicular arrangement of optic fibers is lost in some mammals.
Physiol Rev • VOL
In rodents and carnivores there is a major change in fiber
order in this region, such that uncrossed fibers spread
throughout the nerve mixing with fibers that are destined
to cross (4, 5, 76). The chiasm in these animals is relatively homogeneous, with no obvious internal features,
and the uncrossed fibers remain widespread throughout
each hemi-chiasm. This point is important in understanding the mechanisms that regulate chiasm development, as
if fibers destined to project to different hemispheres are
mixed in the proximal nerve, then spatial factors are
unlikely to determine which hemisphere a fiber projects
into. But if these fibers remain segregated, then such
mechanisms may be significant.
This pattern with crossed and uncrossed projections
being mixed in the proximal nerve and hemi-chiasm is not
ubiquitous in mammals. In marsupials, uncrossed fibers
are confined laterally in the nerve and chiasm with none
approaching the midline. In some marsupials uncrossed
fibers are segregated from fibers from the same eye that
are going to cross the midline by thick astrocytic processes, which demarcate a morphologically distinct lateral region in the far proximal nerve and rostral chiasm.
In this animal the chiasm has a tripartite organization,
having a central core containing crossed fibers and two
lateral segments that appear to have been added on to the
main body of the chiasm, each exclusively containing
uncrossed fibers (80). This finding gave rise to the notion
that there may be a fundamental difference in chiasmatic
organization between eutherian (placental) mammals and
marsupials. Given that marsupials branched from the
main line of mammalian evolution relatively early, this
idea was not difficult to accept (18). Unfortunately, it was
incorrect. Recently, it has become clear that uncrossed
fibers in some eutherian mammals also remain confined
laterally in the nerve and chiasm. Such patterns are found
in tree shrews, which have highly specialized visual systems (81).
There is also strong evidence that uncrossed fibers
remain confined laterally in the primate nerve and chiasm.
Lesions confined to the temporal retina result in degeneration restricted to the lateral nerve and chiasm in Old
World monkeys (67, 68). Naito (105) retrogradely labeled
ganglion cells in Old World primates and traced their
axons. In one example, a group of cells was labeled just
temporal to the fovea. The axons of these cells were
confined to the lateral chiasm with none approaching the
midline. When anterograde tracers are injected into one
eye in similar animals and both nerves and chiasm sectioned horizontally, labeled fibers can be identified segregating into two groups in the anterior chiasm. The medial
group crosses the midline, whereas the lateral group enters the ipsilateral optic tract via a lateral course through
the chiasm avoiding the midline region (61). These anatomical descriptions are consistent with clinical observations in humans. Pituitary tumors that compress the chi-
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
dorsoventral axis in each hemichiasm in terms of whether
fibers have crossed the midline or not. Generally, as optic
axons cross the midline, they adopt a ventral location,
such that progressively through the length of the chiasm
there is a reduction in the dorsal component of fibers that
are waiting to cross, and an increased proportion of fibers
located ventrally that have decussated and are coursing
toward the optic tract. Within this ventral component,
fiber order increasingly adopts the configuration found in
the tract (123). Although there is a paucity of data regarding the path that fibers with different diameters take
through the chiasm in other animal types, there is evidence that the dorsoventral distinction between fibers
that have crossed the midline and those that have not is
common to a range of mammals (68).
There have been two detailed studies undertaken in
old world primates that have traced projections through
the chiasm with either degeneration techniques or using a
retrograde tracer. The first used photocoagulation of defined retinal regions and silver degeneration methods
(68). This revealed that the crossed fibers from peripheral
dorsal and ventral retina cross the midline at different
locations. Fibers from the dorsal retina cross in the caudal chiasm, whereas those from ventral locations tend to
cross more rostrally. Once these fibers have crossed the
midline they enter a lateral region where the chiasm is
laminated, with the decussated fiber groups sandwiched
between fiber groups from the other eye that have not
crossed the midline. The macular fibers were found to
occupy all regions of the chiasm except those in the
inferior rostal and caudal regions but were more concentrated centrally and dorsally.
The second study used retrograde labeling to trace
optic fibers projecting to the LGN (105). It also revealed
that fibers from dorsal and ventral retina cross at different
locations. Fibers from the peripheral ventral retina cross
in more anterior chiasmatic regions than those from the
dorsal retina periphery. The distribution of label from
more central retinal regions in this study were more difficult to interpret.
It is not possible to trace fibers with different axon
diameters in the primate retinofugal pathway in the same
way as in the ferret (123). There is a marked gradient in
ganglion cell size across the primate retina (43, 113). This
is reflected in the axon’s size. Consequently, thick axons
originating from large but more peripheral cells (␤-cells)
cannot be distinguished from axons having a similar diameter that originate from centrally located ␣-cells.
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
III. DEVELOPMENT OF THE
MAMMALIAN CHIASM
A. Potential Mechanisms for Chiasm Generation
Numerous factors probably regulate the development of the chiasm. The relative influence of each of these
almost certainly varies between species. Furthermore, it
is likely that some mechanisms are regulated temporally,
such that they may be influential during one period but
not necessarily in another. Despite this, it is possible to
divide the potential developmental mechanisms into
crude categories that are not exclusive and to some of
which a temporal dimension may be added.
First, it is possible that chiasmatic pathways are
partly specified by retinal location and that the fundamental mechanism has a significant genetic component. Second, it is possible that chiasmatic pathways are established as a consequence of interactions between retinal
axon growth cones and elements in the chiasm that provide critical information in a time-dependent manner.
These elements may or may not be located along the
midline. Third, the pathways may be established by interactions between growth cones from the two eyes along
the midline region, with some interactions being permissive allowing fiber crossing and some being inhibitory
resulting in ipsilateral deflection. Fourth, it is possible
that the temporal domain on its own is critical and that
the time at which a developing fiber enters the environPhysiol Rev • VOL
ment of the chiasm determines which hemisphere to
which it projects. Because these categories are unlikely to
be totally exclusive or universal, they will not be dealt
with in order, but they need to be considered in relation to
the experimental evidence that is available on chiasm
development.
B. Ganglion Cell Generation and Optic
Chiasm Formation
Spatiotemporal patterns of ganglion cell production
are important in chiasm development because cells that
are generated early are most likely to reach the chiasm
before those generated later. As such, early generated
cells are likely to encounter a very different chiasmatic
environment than those that are generated late once this
region is established.
The retina develops with a center to periphery gradient (96, 121, 129, 134). The only significant exception to
this is the accumulation of melanin in the retinal pigment
epithelium (RPE) where this gradient is reversed (12, 13).
There is strong evidence in primates, including humans,
that the maturational focus is the presumptive foveal
region (92, 96, 110, 120), whereas in mammals with less
specialized retinae, such as rodents and marsupials, it is
around the optic nerve head (36, 54, 71, 125). Hence, in
primates, the first ganglion cells to enter the chiasm are
likely to arise from the presumptive fovea, whereas in
rodents they are likely to arise from around the nerve
head.
The difference between the nodal points for retinal
development between primates and rodents appears to be
a real species difference. However, data generated from
carnivores are problematic. A range of studies undertaken
in the cat indicate an area in the upper temporal retina as
being the focus of maturation. This includes not only the
nodal point for ganglion cell production, but also a range
of other developmental events such as the initiation of
layer formation and the location of the first region where
mitotic activity ceases (46, 121, 134, 166). However, experiments undertaken on the ferret clearly demonstrate
that the optic nerve head is the nodal point for ganglion
cell production along with many other features of development (129, 131).
It is possible that within carnivores there is a shift of
the nodal point from the optic nerve head to the presumptive area centralis. This discrepancy may not be understood until a wider range of carnivores has been studied.
It is also possible that real differences exist between
closely related animals depending on other, as yet unidentified, factors. Hence, the nodal point for ganglion cell
generation may vary depending on the gradient of cell
density across the mature retina, its size, or the relative
location of the area centralis. In the cat and primate, the
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
asmatic midline result in a specific loss of visual fields
arising from the crossed projection and only affect the
uncrossed projection when the tumor is very large and the
crossed projection is almost completely lost (59). Compression of the lateral chiasm by aneurysm of the internal
carotid artery results in a loss of visual fields arising from
the temporal retina (32). Hence, there is growing evidence
that the dispersed uncrossed projection found in the
hemi-chiasm in some rodents and carnivores may be
unique to these mammals and that this pathway remains
confined laterally in most other mammalian types.
These findings support the notion that there is probably not a prototypical mammalian chiasm in terms of the
course adopted by uncrossed fibers. This has important
ramifications for mechanisms that regulate pathway selection. The potential mechanisms determining whether a
fiber remains uncrossed or crosses the midline are likely
to be very different depending on whether it is mingled
with fibers that will behave in a similar fashion or not.
Unfortunately, to date, research on chiasm development
has almost exclusively been confined to animals in which
the projections from each eye are mixed in the proximal
nerve and hemi-chiasm (5, 6, 45). Hence, our picture of
chiasm development may have to be revised.
1399
1400
GLEN JEFFERY
Physiol Rev • VOL
small, making an analysis of their spatio-temporal pattern
of production difficult.
Patterns of ganglion cell production can be related to
the distribution of axons of different size across the chiasm, providing a chronotopic history of chiasmatic development. In the ferret, ␤-cells are the first to be generated,
and their medium-sized axons are located caudally in the
chiasm. As ganglion cells are generated with a center to
periphery gradient (121, 129), axons arising from ␤-cells
from the central retina should be located toward the
caudal pole of the chiasm and those from more peripheral
regions deeper in the chiasm. The ␣- and ␥-cells are
generated later, and their respective large and fine axons
are found at more rostal locations than the majority of
axons from ␤-cells (123, 124). Axons from ␣- and ␥-cells
from the retinal periphery should be located toward the
rostral pole of the chiasm. Hence, cells generated early in
development are found caudally in the chiasm, whereas
those generated later are located rostrally. This provides
strong evidence that the chiasm develops along a caudal
to rostral gradient.
These patterns of cell generation can also be related
to the organization of fibers as they leave the chiasm and
enter the optic tract. Fiber addition in the optic tract
occurs preferentially along the pial surface, such that
older fibers are displaced by younger ones into deeper
regions away from the pia (165). Medium-sized fibers
originating from ␤-cells are found deep in the tract,
whereas large and small fibers are located more superficially (51). Analysis of the distribution of axons of different size through the chiasm has not been undertaken in
another animal model. Despite this, a range of studies
undertaken on the cat, rat, and primate have confirmed
that different-sized fibers are differentially distributed in
the optic tract but not in the nerve (35, 51, 122, 127, 128).
Patterns of ganglion cell generation in rodents and
carnivores also become of interest when ganglion cells
are segregated into those projecting to separate hemispheres rather than into different cell types. In these
animals the temporal retina contains cells with crossed
and uncrossed pathways. Although there is a center to
periphery pattern of ganglion cell production, the cells
destined to remain uncrossed through the chiasm are
generated in front of the expanding wave of cell generation. Hence, in the temporal retina, they are produced
before cells at similar eccentricities that will project
across the midline. This has been demonstrated with
different methods in mouse and ferret. In the mouse,
patterns of ganglion cells production have been marked
with [3H]thymidine and their chiasmatic pathways identified at maturity by tracer injections into one side of the
brain (Fig. 2). Ganglion cell generation in the mouse
occurs across embryonic days (E) 10 –19. Birth occurs
around 21 days after conception. The peak in the production of uncrossed cells occurs on E13, whereas for
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
retina is large, gradients in cell density are steep, and the
region of peak cell density is located closer to the nerve
head than the temporal periphery (70). In the ferret, ganglion cell density at the area centralis is only half of that
in the cat, and this region is located closer to the retinal
periphery than the optic nerve head (57, 151).
Despite such differences, ganglion cell production in
all animals occurs in a crude center to periphery pattern
that harbors three separate but overlapping waves. It has
been shown in a wide range of mammals that different
ganglion cell classes are generated at different stages (2,
120, 125, 132, 139, 167). These studies commonly rely on
the use of [3H]thyminde injected during development to
identify the time at which cells leave the cell cycle. The
cells are then classified into one of the three main ganglion cell classes at maturity on the basis of soma diameter, or morphologically following retrograde tracer labeling. Unfortunately, in many mammals, distinctions
between ganglion cell types based on soma diameter are
poor, and there are few studies in which there is a sharp
picture of relative patterns of cell generation in the ganglion cell subtypes. Furthermore, it is only in the ferret
that there is an understanding of the patterns of axon
projection of the different ganglion cell types through the
chiasm region, so as to be able to relate these to patterns
of cell generation.
In the cat and ferret there is some agreement regarding the relative patterns of ganglion cell production at
defined retinal locations. In the cat, cell classification
based on ganglion cell soma size is relatively reliable
(171). In this animal, medium-sized cells are produced
before the larger cells, whereas small cells are produced
thoughout the period of ganglion cell production (166,
167). This corresponds to ␤-cells being produced first,
followed by ␣-cells, while production of ␥-cells occurs
throughout (171). In the ferret a similar relationship exists
between patterns of production of ␤- and ␣-cells. But,
unlike in the cat, small ganglion cells, probably corresponding to ␥-cells, are generated in a wave that follows
the ␤- and ␣-cell populations (132).
Two problems hinder a full picture of ganglion cell
development in these animals. First, studies have been
undertaken on whole-mounted retinae, sectioned parallel
to the retinal surface. Because of the large size of the cat
retina, analysis has been focused on central retinal regions, with only limited sampling in the periphery (166).
This confined topographic sampling may explain the authors proposition that the center to periphery spread in
patterns of cell generation is not in the form of a crude
annulus as reported in other animals (36, 54, 125, 132), but
appears as a spiral focused around the area centralis.
Second, the ␣-cell population in the cat and ferret retina is
relatively small, accounting for ⬃5% of the total ganglion
cell population (112, 171). Hence, the number of cells
labeled at any one stage of development will always be
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
1401
FIG. 2. Schematic representation of the patterns of
ganglion cell generation in cells giving rise to the crossed
and the uncrossed projections in the mouse between embryonic days (E) 11 and E19. The border of the temporal
retina from which uncrossed cells arise is marked by the
dashed line. Ganglion cells are generated in a crude center
to periphery pattern. However, uncrossed cells in the temporal retina are generated abnormally early within this
pattern. Most of the uncrossed cells are generated around
E13, which is before the main wave of cell production that
gives rise to the crossed projection from this location. n,
Nasal; t, temporal. [From Dräger (36).]
Physiol Rev • VOL
chiasmatic pathway selection, such mechanisms are restricted to only a limited range of mammals.
C. Axon Extension and Morphological
Development of Retinal Axons
Optic axons extend during maturation via the progressive development of their growth cones along the
optic pathway. These consist of a flat central area from
which filopodia extend outward. Between the filopodia
there are ruffled membrane regions, lamellipodia. The
filopodia are active and are constantly extending and
retracting as the cone moves and the axon extends.
Growth cones play an active role in enabling the
developing axon to navigate through regions where pathway choices must be made. In the rodent retinofugal
pathway, the morphology of the growth cones varies
markedly depending on its location. Hence, along the
course of the optic nerve the growth cones tend to have a
relatively simple morphology, whereas in the region of the
chiasm and close to their target structures where choices
must be made, they are more extensive and morphologically complex (14). Similar results showing that growth
cones have more filopodia when they encounter decision
points have been obtained in both mammalian and nonmammalian species and in a wide range of systems (86).
Evidence that growth cone filopodia play a critical
role in optic pathway guidance has come from studies
undertaken on the retinofugal pathway of Xenopus embryos. Exposed brain preparations were maintained in
vitro, and cytochalasin B was added to the medium. This
drug disrupts microfilament cores of filopodia, resulting
in retraction of the filopodia, but leaves the lamellipodia
intact. The optic tract in these preparations became disorganized with the majority of fibers being unable to
locate the tectum. Unfortunately, the optic chiasm was
not examined specifically, although the authors report
that some fibers growing through this region stalled with
drug application (22).
Optic nerve growth cones appear to advance at a rate
of ⬃60 –100 ␮m/h (26), but there is evidence that this rate
of growth may not be uniform along the length of the
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
crossed cells in the temporal retina it was 2 days later on
E15 (36).
In developing ferrets, ganglion cells have been retrogradely labeled from one optic tract or their axonal pathways marked anterogradely by placing a tracer in the
temporal retina. Early in development, ganglion cells in
the temporal retina were only found to project to the
ipsilateral optic tract, whereas later cells within this region projected bilaterally. Likewise, early in development
only uncrossed cells could be labeled in the temporal
retina from the ipsilateral optic tract, with no label found
at similar temporal eccentricities in the contralateral retina. However, labeled cells were found at these locations
in the contralateral retina later (6). Hence, not only do
ganglion cells that are destined to remain uncrossed arise
relatively early for their retinal eccentricity, but their
axons also extend into the chiasm before those from
similar locations that are destined to project across the
midline.
Taken together, these studies demonstrate that
within the temporal retina, cells that remain uncrossed
through the chiasm come out of the cell cycle before
those that will project across the midline. Hence, it is
possible that uncrossed cells could be partly specified in
terms of the number of cell cycles they go through or the
point at which they exit the cell cycle in relation to their
location. This point will be relevant when abnormalities in
patterns of cell generation and chiasm formation are considered in albinism (see sect. IV).
The pattern of cell generation in the primate is markedly different from that found in rodents and carnivores.
Here, ganglion cell generation is roughly symmetric
across the naso-temporal division, with no indication that
uncrossed cells that arise exclusively from the temporal
retina are generated before contralaterally projecting
cells that reside on the nasal side of the division (92). The
only other comprehensive studies of ganglion cell generation in mammals have been undertaken in marsupials.
Again, in these animals there is no indication of asymmetric patterns of cell production in the temporal retina (2,
54). Hence, if differences in the time of cell generation for
crossed and uncrossed ganglion cells are significant in
1402
GLEN JEFFERY
Physiol Rev • VOL
131). The finding that new growth cones pass preferentially through the rostral chiasm is consistent with studies
that have compared the differential distribution of various
axon sizes across the chiasmatic midline in relation to
patterns of ganglion cell production. This is consistent
with the evidence that the chiasm develops caudorostrally (123, 131).
Unfortunately, during development it is not possible
to differentiate the different ganglion cell classes on the
basis of axon size, because at these stages they are uniformly thin, with no morphological criteria for differentiating them. Because of this, it is not possible to determine
whether the cells that will mature into the separate ganglion cell classes have different rates of axon growth or
distinctive growth cone morphologies. Differential
growth during the postnatal period results in the fiber
spectrum seen in the adult (11, 26).
Many more retinal ganglion cells are produced than
are found in the adult. There are approximately twice as
many optic axons at early stages compared with the number found at maturity (109, 114, 177). Behind the eye these
fibers appear to be arranged in a retinotopic pattern as far
as the four retinal quadrants are concerned (21). Hence,
the cells destined to die during the period of natural
ganglion cell death are not organized in a nontopographic
manner. Detailed examination of individual growth cones
and fibers has been undertaken in the developing monkey
nerve. This showed that within specific regions, growth
cones and fibers lost half of their original neighbors over
a distance of only 8 –10 ␮m. A total of 500 serial, transverse, ultra-thin sections were collected, and between the
first and last sections of the series 92% of all initial contacts were lost. Furthermore, in the majority of cases the
fibers touched by growth cone filopodia had no common
neighbors (181). Hence, although there appears to be
quadrant specific order, optic nerve fibers do not maintain
a particular group of immediate neighbors during outgrowth, but are highly promiscuous within subregions of
the nerve.
The retinotopic pattern of fiber organization is
eroded along the length of the developing mouse optic
nerve, and closer to the chiasm there is a major reorganization of the axon population (21). The change in order
seen proximally marks the location where new growth
cones segregate from being mixed with older nerve fibers
to adopt a more exclusive ventral location adjacent to the
pial surface. In the ferret, this change in fiber order is
associated with a change in glial organization (Fig. 3). In
the distal nerve, glial cells have an interfascicular distribution, with axon bundles separately encircled by glial
cytoplasm. In the proximal nerve, chiasm, and optic tract,
glia adopt a periventricular location with radial processes
projecting down to the subpial surface. These processes
pass between axon groups. The boundary between these
two regions of glial organization shifts during develop-
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
pathway (45). In the fish optic nerve it has been proposed
that the rate of fiber development changes as optic nerve
fibers move between different glial environments (95). In
the mouse the crossed and uncrossed pathways appear to
travel at different rates between the eye and the optic
tract. Uncrossed cells take ⬃5 days between leaving the
cell cycle and their axons entering the optic tract,
whereas cells generated at the same time but projecting
contralaterally take only 3 days before entering this region (26, 36). It is possible that this difference can be
partly accounted for by different types of interaction
between the two fiber populations in the chiasm
(see sect. III H).
Growth cones can be found in all regions of the
developing optic nerve, although there is evidence that
more are found in peripheral regions than toward the
nerves core, reflecting the rough center to periphery gradient in ganglion cell production. Growth cones do not
accumulate exclusively along preexisting bundles (26,
177, 178). In more proximal regions the new fibers accumulate in the superficial subpial regions between the
endfeet of radial glia. It has been suggested that the
growth cones use the stems of the radial glia at the
junction between the nerve and chiasm as a substrate for
directed growth (52). Despite this, growth cones in the
superficial regions tend to be associated with one another
rather than to the processes of the glia. Because there is
no clear trend for growth cones to travel along radial glial
processes over extensive distances, it is unlikely that they
move toward the pial surface along the stems of these
cells (24).
In the chiasm the glial endfeet line the surface of the
chiasm and separate fibers from the underlying basement
membrane. The membranes of adjacent neuronal and glial
processes have regions of specialization. These have been
termed omega profiles and occur between axons or
growth cones and glial processes. They are identified as
membrane thickenings on radial glia processes that are
invaginated. Within the invaginations growth cone processes can be found. However, there appears to be no
fusion of the growth cone membrane with that of the
radial glial cell, although dense material can sometimes
be found spanning the cleft between the two membranes.
On the basis of an analysis of the spatial distribution of
these profiles it has been suggested that they represent
the basis of a signaling mechanism that results in growth
cones losing their preference for travelling among radial
glial endfeet (24). This represents a transition away from
the chronotopic distribution of fibers present prechiasmatically.
It was originally proposed that growth cones advanced through the chiasm exclusively along the pial
surface (14, 164). It now appears that they can be found
through the full depth of the rostal chiasm, with a tendency to be more numerous toward the pial surface (24,
1403
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
ment with the interfascicular region progressing toward
the chiasm with development (52). The age-related patterns of fiber order seen in the chiasm and optic tract can
be understood in relation to this arrangement.
One aspect of the developing nerve and chiasm that
has not been widely appreciated is the changing configuration of this region during optic ingrowth. When the first
optic fibers enter the chiasm, the eyes of the embryo are
more laterally placed than at later stages of development.
Hence, the first fibers at the chiasm, which arise from
central retinal regions of each eye, meet almost head on
as the nerves approach the midline at ⬃90° to it. This
occurs within a relatively loose cellular environment.
Later in development, the angle between the two nerves
declines markedly. Around the time of birth, when in
rodents the last ganglion cells are being generated in the
peripheral retina (36, 71), new fibers grow through a much
tighter environment and approach the midline at ⬃30 – 40°
(87, 137). It is not known whether this change in the
configuration of the chiasm affects the probability of a
cell crossing the midline or not. However, it may result in
differential patterns in fibers that do cross, as early decussating fibers would be expected to cross the midline at
an angle close to perpendicular, while later decussating
fibers would be expected to cross at a more acute angle.
Physiol Rev • VOL
D. Adhesion Molecules and Pathway Markers
A substantial body of literature exists on the role of
agents that provide adhesive or repellent surfaces that
influence the direction of fiber growth both in vivo and in
vitro (84, 133). Such agents have been shown to be important in the regulation of midline commissural pathways (140, 149, 150, 152), and although there is little doubt
that these, or related agents, probably play a role in
chiasm development, there is only limited understanding
of what it might be. Consequently, no attempt will be
made here to review this literature comprehensively as
this has been done well by others (150).
Optic nerve fibers grow out from the eye in fascicular
groups, with contact between them mediated in part by
membrane glycoproteins. The first of these glycoproteins
to be identified was neural cell adhesion molecule
(NCAM) (84). In both bird and mammal, the course of the
optic pathway from the eye into the brain is marked by
the presence of NCAM. In chicks NCAM is present on
neuroepithial cells and preferentially distributed on the
marginal endfeet of the radial glia, which are contacted
directly by optic growth cones (141). That this molecule is
important in the regulation of patterns of fiber order along
the pathway is demonstrated by the finding that intraoc-
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
FIG. 3. Schematic representation of
the change in fiber order found in the
developing proximal nerve in relation to
the change in glial organization. The axons are indicated in order of age, 1 being
the oldest. The first four are shown as
interrupted lines, and these reach the
border between the two types of glial
organization (interfascicular and radial)
early, when the border was close to the
optic foramen. The next three are shown
as continuous lines, and these reach the
border later, when it was closer to the
brain (to the right of the figure). It is
postulated that the developing axon tips
move toward the pial surface when they
reach the radial glia and that the partial
reversal of order is produced by this and
by the shift in the border of the glial
types. [From Guillery and Walsh (52).
Reprinted by permission of Wiley-Liss,
Inc., a subsidiary of John Wiley and Sons,
Inc.]
1404
GLEN JEFFERY
Physiol Rev • VOL
the chiasm (27), although the limited experimental evidence available does not support this idea (130).
Chondroitin sulfate proteoglycans (CSPGs) are extracellular matrix molecules that appear to provide an
unfavorable environment for axon growth and have been
implicated in the changing patterns of fiber order in the
developing retinofugal pathway (16). The differential distribution of CSPGs during development appears to compliment the chronotopic segregation of axons in the optic
pathway and the underlying change in glial architecture of
this region. Other cell adhesion and exracellular matrix
molecules have been examined (L1, NCAM, and TAG-1)
and appear to show no differential distribution related to
changes in fiber order. CSPGs are present in older groups
of optic fibers, but not in newly developing ones (130).
These agents may act by providing a relatively unfavorable environment for axon addition, perhaps by disrupting adhesion molecules that promote fiber growth. In
support of this idea, it has been demonstrated that both
the glial architecture and the pattern of CSPG’s labeling
form as a consequence of the arrival of the first optic
fibers, but fail to occur in the absence of optic fibers (130).
That these molecules are involved in pathway selection at
the chiasm is confirmed by observation that their removal
in tissue slices results in many axons deviating from their
normal course (23).
Roundabout (Robo) is a transmembrane receptor
identified in Drosophila that is expressed on axons. It is
involved in preventing ipsilaterally projecting axons from
crossing the midline and commissural axons that have
crossed the midline from recrossing (88). It is a receptor
for a midline repellent molecule termed Slit, which has
been identified as an inhibitory extracellular matrix molecule that is secreted by midline glia. Robo and Slit both
have variants. Slit2 collapses and repels retinal ganglion
cell growth cones. In rodents it is expressed at a range of
locations but is absent from the ventral midline in the
regions where the chiasm forms (108). The spatial and
temporal expression of Slit and Robo are consistent with
their playing a role in chiasm formation (41). However,
the nature of this role has yet to be defined.
E. Genetic Regulation of Chiasm Development
An increasing number of genes are being identified or
implicated in the mouse as players in the development of
the visual system, but only those directly relevant to the
problems addressed here are considered. The Pax family
of genes encodes a highly conserved group of transcription factors (Pax1 to Pax9, Ref. 168). These genes have
dynamic patterns of expression in the developing nervous
system, and it has been proposed that they play a role in
defining regions and regulating differentiation of the neural primordium (47).
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
ular injection of anti-NCAM in the chick results in distortion of growth cone-neuroepithelial cell relationships
leading to a disruption of fiber order in the optic pathway
(141). This supports the idea that NCAM plays a role in
axonal fasciculation and substrate adhesion, although
doubts have been raised regarding its role in directional
guidance. Considerable additional evidence in favor of
this comes from work on fasciclin II, which in Drosophila
is the immunoglobulin most similar in structure to NCAM.
Less evidence is available for the mammal, although its
presence is consistent with this notion (161).
NCAM is expressed along the length of the ferret
visual pathway during development but appears to be
distributed differently in the nerve when compared with
the optic tract (130). In the nerve, NCAM distribution is
axonal and around fascicular groups, whereas in the tract
it is diffuse. In the chick, NCAM is present on the surface
of radial glial endfeet along the visual pathway (141).
However, this is not the case in mammals (132). Hence, it
is unlikely that this molecule is responsible for the change
in fiber order found in association with a change in glial
organization in the proximal nerve (6, 50). Despite this,
evidence that it may play an important role in the development of this pathway is underlined by the finding that in
the chick, blocking NCAM results in degradation of fascicular order in the nerve, and of nerve fiber order along
the length of the optic pathway. However, there is no
evidence that it disrupts pathway selection (157).
It has been possible to look at the effects of mutations in NCAM and its isoforms in mice. Surprisingly, the
effects of such mutations have been very limited, and in
general have not resulted in significant disruptions to
developing fiber pathways in the brain. This implies that
multiple adhesion systems may be responsible for the
development of fiber pathways, and it is probable that
when one agent is removed genetically, others may have
the capacity to take its place. To complicate matters
further, these agents may have different effects at various
time points in development. Hence, a knock-out model for
investigating these molecules may not be as suitable in
revealing their functions as was originally thought (161).
Although we know little about adhesion molecules
and markers in the chiasm, this is a rapidly expanding
field, and any review of them will soon be dated. Information from other systems reveals that some markers
appear to change in relation to the midline. In the spinal
cord the cell surface glycoprotein TAG-1 is expressed by
axons that will cross the midline, but not by those that
will not cross. After crossing, TAG-1 expression ceases
and these fibers start to express the immunoglobulin L1
(34). L1 is expressed in optic axons that are grouped into
fascicular bundles and by their growth cones, but not by
the growth cones that are in contact with glial cells (8). It
has been proposed that L1 may be playing a part in the
changing relationship present as optic fibers pass through
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
of chiasm formation has been identified in zebrafish with
mutations of No-isthmus, which is a transcription regulator that is highly homologous in sequence to Pax2 (94).
An inability to form an optic chiasm has been reported in both dogs and in some human conditions. A
strain of Belgian sheep dogs has been found to be achiasmatic. These animals have relatively normal retinae and
optic nerves; however, each optic nerve projects only into
the ipsilateral hemisphere without the formation of a
chiasm (58, 180). Achiasmatic humans were first reported
by Vesalius in 1543 (see Ref. 3 for discussion). More
recently, Apkarian et al. (3) have documented two cases
of “nondecussating retinal-fugal fiber syndrome.” These
individuals are not albino and have a normal fovea and
macular region, which are commonly underdeveloped in
albinos (77). Unfortunately, nothing is known about chiasmal development in either these dogs or humans.
The spatial domains of a range of other regulatory
genes have been mapped in relation to the development of
the chiasmatic region. Lateral to the midline retinal axons
course along part of the Nkx-2.2 domain in a region that
overlaps with expression domains of BF-2 and Dlx-2.
Closer to the midline the axons traverse a zone of overlap
between Nkx-2.2 expression and BF-1 expression (99).
However, it is not clear whether these domains influence
retinal ganglion cell trajectory or not, as the authors
themselves point out that changes in axon pathways are
commonly associated with boundaries of, or interfaces
between expression domains, which was not clearly the
case here.
F. Role of Chiasmatic Neurons in Chiasm
Pathway Selection
Before the arrival of optic axons at the mouse chiasm
(E11–E12), cells expressing a range of neuron-specific
markers can be identified in the ventral diencephalon in
the region that will develop into the chiasm. They are
organized in a V-shaped pattern with the tip of the V
located at the midline and pointing anteriorly. These cells
FIG. 4. Schematic diagram of the patterns of Pax-2 and Sonic hedgehog (Shh) expression in the mouse retinofugal
pathway. At E9.5 Pax-2 is expressed along the optic pathway, but at this stage it does not approach the chiasm, where
Shh is expressed. At E11.5 Pax-2 expression is continuous across the midline through a gap in Shh expression. If Shh
expression is maintained across the midline at E11.5 in a mutant, optic axons are unable to cross and project ipsilaterally.
vh, Ventral hypothalamus; poa, preoptic area. [From Torres et al. (160). Reprinted with permission of the Company of
Biologists Ltd.]
Physiol Rev • VOL
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
Pax6 is also expressed early in the developing mouse
anterior neural plate and optic vesicle. Mutations in this
gene were found to be responsible for small eye mutants
in animals and for some being born without eyes (119).
Targeted expression of this gene has also been shown to
result in the development of ectopic eyes (53).
Similarly, Pax2 is expressed in the developing mouse
eye. It is present in the ventral half of the optic vesicle but
is lost when the retina invaginates. However, it remains
along the borders of the choroid fissure and extends into
the ventral half of the optic stalk at E9, which is just
before the first optic fibers accumulate along the nerve.
The region of the ventral forebrain where optic fibers will
create the chiasm is formed at roughly this stage by
neuroepithelial cells that express the Sonic hedgehog
(Shh) gene, which marks the midline region. Optic fibers
progress toward the chiasm within an optic stalk that
continues to express Pax2. As the fibers from each eye
enter the midline region, Pax2 expression becomes continuous from one eye to the other eye across the midline,
but at this stage Shh expression is lost (Fig. 4, Ref. 160).
The fact that these patterns of expression are important for development of the chiasm is reflected by the
consequences of generating a Pax2 null mutant. In this
situation the optic fissure fails to close, the separation of
Shh expression along the chiasmatic midline is less
marked, and optic fibers project directly into the ipsilateral optic tract with none crossing the chiasmatic midline.
In these animals, pigmentation at the back of the eye
extends throughout the length of the optic sheath, and
cells of the optic stalk do not proliferate. As a result, the
mutant nerve is devoid of glia. This is of interest given
that glia play such an important role in changes in fiber
order and pathway selection (see above). However, the
significance of their absence in this situation has not been
determined (160).
Mutants of the Pax2 gene in nonmurine species also
show CNS defects. In humans, the mutation is associated
with coloboma and a range of serious visual defects (135),
although to date the optic chiasms of these individuals
have not been examined. Disruption to the normal pattern
1405
1406
GLEN JEFFERY
G. Role of Chiasmatic Glia in Chiasm
Pathway Selection
In rodents and carnivores fibers from the temporal
retina that will remain uncrossed are already distinctive,
as they are generated relatively early given their eccentricity, and probably enter the chiasm at a stage before
those from similar eccentricities that will cross. Hence,
any mechanism invoked to explain pathway selection has
to be viewed within a temporal context. Furthermore, in
these animals, fibers destined to project to different hemispheres are mixed in the proximal nerve (see above).
Hence, spatial factors cannot be significant in pathway
selection, and such cells may need additional information
before they are able to select an appropriate pathway.
Significant advances to understanding the factors regulating chiasmatic pathway selection in the mouse have been
made by the ability to label axons and view the chiasmatic
region in real time in isolated brain preparations. Under
these conditions it is possible to monitor the behavior of
individual growth cones in relation to the midline between E15 and E17 (45).
In such preparations, growth cones in the chiasm
have been shown to have phases of rapid advance alternating with periods in which they pause. All optic growth
cones, irrespective of whether they ultimately cross the
midline or not, appear to approach this region. When
adjacent to the midline, they pause for periods of several
Physiol Rev • VOL
hours. During these periods, the growth cones remain
highly mobile, extending and retracting their filopodia.
Those that turn to project ipsilaterally have markedly
extensive filopodia that are constantly being remodelled.
On turning away from the midline they retract the filopodia that were extending proximally and extend a single
process away toward the ipsilateral optic tract, which
becomes its leading edge. These growth cones continue
toward the ipsilateral tract with a much simpler morphology than they possessed at the midline region (45). These
results are intuitively appealing, particularly in the light of
the need for fibers to obtain information before committing themselves to a specific pathway. However, they are
not in agreement with those of Sretavan and Reichardt
(148), who using similar methods failed to find evidence
of significant pausing of uncrossed axons before they turn
at the midline.
The fibers that cross the midline do so at all dorsoventral locations and are not restricted to crossing along
the subpial region (131). When they cross the midline,
growth cones mingle with relatively mature fibers that
have already crossed, but initially remain confined within
monocular fascicles lacking glia. This pattern of organization degrades further from the midline (24, 27). These
results strongly suggest that in these animals there is a
midline signal that ingrowing fibers must read to make the
correct pathway choice. This notion has received some
support from a study in which developing cells from
different retinal regions in the mouse were cocultured
with those extracted from the chiasmatic region (169).
Cells from the temporal retina from which the uncrossed
projection arise that were removed at E15 and maintained
for 1–5 days were markedly reluctant to grow across
chiasmatic cells compared with those derived from other
regions. The reduction in neurite outgrowth and neurite
length was ⬃50% in the cells taken from the temporal
retina compared with those from other areas.
Although this finding is consistent with results obtained in isolated brain preparations (45), there are difficulties with its interpretation. Within the adult rodent
temporal retina, 75% of ganglion cells still project across
the midline (30, 78) and should have been present in these
preparations as the majority of crossed and uncrossed
temporal cells would have been generated by the time the
extracts were taken (36). Hence, the magnitude of the
effect is significantly larger than would be expected as the
majority of fibers from this region project across the
midline. Furthermore, at the stage of development studied, there is a significant transient uncrossed projection
from outside the temporal retina from cells that do not
survive to maturity (25, 74).
It is possible to divide the developing chiasm into a
series of glial domains that differ architecturally and in
terms of the composition of their intermediate filaments.
There are differences in patterns of vimentin staining
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
express two factors affecting neuronal outgrowth: 1) an
immunoglobulin, L1, which is known to promote retinal
ganglion cell outgrowth; and 2) a glycosylated cell surface
molecule CD44, which has an opposing inhibitory effect
on retinal axon outgrowth. It has been proposed that
these cells act as a chiasmatic template (145, 148).
Incoming optic axons do not enter or cross regions
where neurons express these markers. Rather, they turn
away from them to form the cross-shaped morphology of
the chiasm. The fact that these cells play a role in chiasm
formation is demonstrated by the consequence of their
selective removal with an antibody to CD44 at E11. Following this manipulation it is reported that optic axons
fail to advance just before the point of fusion of the two
optic nerves (147).
The expression of GAP-43 in developing retinal axons is also critical for normal development of the chiasm.
In GAP-43 knock-outs, retinal axons appear to be delayed
in crossing the chiasmatic midline. However, more importantly, once across the midline they fail to progress normally through the region between the chiasmatic midline
and the optic tract, resulting in disorganized patterns of
trajectory into each hemisphere. There is evidence that
this is retinal ganglion cell specific and may be restricted
to specific developmental stages (91, 146).
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
Physiol Rev • VOL
caudal end of the developing chiasmatic region, whereas
those that cross later tend to pass further rostrally (98). In
each case, growth cones move away from radial glial
endfeet at the midline toward the ventricular zone (24).
During the main period of axon ingrowth (E15–E17), cells
that project contralaterally enter the palisade of RC2 positive cells and progress across the midline, while cells
destined to remain uncrossed from the temporal retina
turn within the palisade, but do not enter the SSEA-1
positive region. At this stage all growth cones appear to
make contact with the processes of these cells (97). However, it has been shown that there are two components to
the uncrossed pathway: the first from the central retina
lost during development and the second from the temporal retina (25). The former group enters the ipsilateral
tract without approaching the midline. It is unclear why it
is possible to generate an early uncrossed pathway without midline interactions, which are necessary when the
uncrossed projection arises from the temporal retina.
This may be related to the changes in the geometry and
cellular environment of the mouse chiasm between E12
and E15.
It is clear that growth cones and axons communicate
and that the information derived is used to assist pathway
selection. What is not clear is the route by which this
communication might occur. This question remains
largely unanswered. It is becoming increasingly apparent
that in the adult, optic axons and glia are able to communicate without any form of anatomical specialization, possibly via the diffusion of chemicals that they release.
There is evidence that glutamate may play a role in this
(90). Furthermore, mGluR3 receptors have been localized
to optic nerve astrocytes but not oligodendrocytes (82).
Astrocytes are generated before oligodendrocytes during
the period of chiasm formation (144), and their processes
have been shown to form the boundaries between crossed
and uncrossed axons in the marsupial chiasm (56).
H. Interactions Between Fibers From Each Eye
at the Developing Chiasm
Interactions between the fibers from both eyes at the
chiasmatic midline are important for the development of
the normal partial pattern of decussation found in rodents
and carnivores. If one eye is removed early in development while optic fibers are still growing through this
region, the normal pattern of partial decussation at the
chiasm is systematically disrupted. In rodents, only a very
small number of axons project ipsilaterally (37, 74). However, following early monocular enucleation at E12, before significant chiasm formation, the number of uncrossed cells found at maturity is reduced by almost 50%
(44). Similar results have been found in ferrets (19).
Monocular enucleation at E16 and later in the mouse
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
marking two transition zones in the glial architecture
along the ferret optic pathway. The first occurs between
the developing optic nerve and the chiasm, and the second occurs between the chiasm and the tract, with the
former being associated with the gradual transition from
an interfasciclar glial arrangement to a radial glial pattern.
Later, labeled processes can be identified running dorsoventrally through the body of the chiasm. Subsequently,
glial fibrillary acidic protein (GFAP)-positive processes
appear that are confined to the chiasmatic midline. Although these processes mark the midline as a distinctive
cellular region, their appearance is relatively late, occurring after the majority of optic axons have grown through
this region (131).
In marsupials, crossed and uncrossed fibers are segregated in the proximal nerve and through most of the
chiasm, with uncrossed fibers confined laterally from the
main body of the chiasm by a thick vertical band of
astrocyte processes. During development, as the fibers
destined to remain uncrossed approach the chiasm, a
population of distinctive glial cell bodies can be identified
at the lateral chiasmatic margins. At this stage there are
very few other chiasmatic cell bodies present. Uncrossed
fibers pass lateral to these cells, while those destined to
cross the midline pass medially. After the uncrossed projection has grown through the chiasm, the distinctive
concentration of lateral glia can no longer be clearly
identified, although their processes persist (56).
Developing fibers appear to respond to midline cues,
and specializations have been identified in the developing
mouse chiasm that may be the source of these signals.
When the mouse chiasmatic region is stained with an
antibody for mouse embryonic radial glial cells (RC2), a
palisade of radial glial processes can be identified ⬃100 –
200 ␮m wide either side of the midline. Within this palisade, and confined to the midline, is a thin band of separate processes that express a different marker, a stage
specific antigen (SSEA-1). The morphology of these two
populations is different. When sections are stained for
both RC2 and SSEA-1, and the course of individual axons
is traced in relation to these patterns of staining, it is
possible to trace fiber trajectories in relation to the glial
palisade (95). Early axons enter the mouse chiasmatic
region around E12–E13. The first uncrossed cells do not
approach the midline but turn directly into the ipsilateral
optic tract. They arrive in the ipsilateral tract before
axons from the contralateral eye (98). A similar observation has been made in the developing primate chiasm
(102). Hence, these cells navigate into the tract without
information derived from the midline or from any interactions with fibers from the other eye. Many of these
uncrossed cells do not originate from the temporal retina
as in the adult, but from more central regions and do not
persist beyond the late prenatal stage (25).
The first axons to cross the midline do so at the
1407
1408
GLEN JEFFERY
Physiol Rev • VOL
or segregated are associated with fundamentally different
mechanisms of chiasm formation. In the former, optic
axons require information from the chiasmatic environment before selecting their pathway. In the latter group
axons do not appear to need such information.
IV. CHIASMATIC ABNORMALITIES FOUND
IN ALBINISM
Hypopigmented mutants have systematic abnormalities in their chiasmatic pathways. In all albino mammals
that have been studied, there is a shift in the naso-temporal division of the retina toward the temporal periphery,
with a population of ganglion cells that would normally
project ipsilaterally, projecting inappropriately to the contralateral side of the brain. This results in abnormal binocular maps in central visual structures (49). This is not
the only abnormality, because there is a rod deficit and
the central retina is underdeveloped (77, 79). Deficits
associated with albinism appear to be the preserve of
mammals (83). However, not all mammals are affected as
the central retina of the albino squirrel is normal. This
may be related to the fact that this animal is highly
unusual among mammals in having a cone dominated
retina (42).
A. Role of Temporal Ordering in Patterns
of Retinal Cell Addition and Outgrowth
Two factors provide evidence that the focus of the
albino abnormality is located in the retina rather than in
the chiasm. First, there are significant differences in the
organization and development of the chiasm between
rodents and carnivores on the one hand, and marsupials
on the other. However, albinos in both groups of animals
show an abnormally small uncrossed projection (48, 49).
Hence, chiasmatic structure is not important for the development of the abnormality. Second, when developing
retinal axons are grown in vitro and presented with cells
from the immature chiasmatic region, no differences in
patterns of growth can be found between growth over
cells derived from pigmented compared with albino animals (100). Consequently, it is unlikely that albino chiasmatic cells produce a chemical signal that differs from
that found in normally pigmented animals.
It has previously been claimed that there are differences in fiber organization in the optic stalk during development between pigmented and albino rodents and that
ectopic fibers from the temporal retina are misrouted at
the chiasm (142). However, this has been shown to be
incorrect, and the patterns of outgrowth from the eye are
the same in both types of animal (28). Also, no significant
differences have been found in the organization of the
uncrossed projection through the nerves of these animals
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
results in an increase in the number of uncrossed cells
from the remaining eye by ⬃25% (44). This probably
occurs because fibers projecting ipsilaterally at this stage
enter visual structures that have had their major input
removed due to the loss of the much larger crossed
projection. The resulting increase in available trophic
factors/space is probably responsible for the reduction in
the magnitude of the wave of natural ganglion cell death
(44, 74).
These results are in marked contrast to those of
Sretavan and Reichart (148) who find evidence that midline fiber interactions can produce axon turning in the
mouse, but not necessarily toward the optic tract. Moreover, they failed to find any significant change in the
chiasmatic projection from the remaining eye if the other
is removed during early chiasm formation. There is no
obvious explanation for this result, which is in marked
contrast to the findings of Godement et al. (44) and those
undertaken in ferret (50, 156).
Studies of early eye removal in ferrets by Taylor and
Guillery (156) examined animals before the main phase of
natural ganglion cell death in the remaining eye. During
early stages, uncrossed cells arise from both the temporal
retina and more central regions, with the central uncrossed projection being generated before that from the
temporal retina (20, 25). The projection from more central
regions is lost as a consequence of natural cell death.
Early enucleation results in almost total absence of an
uncrossed chiasmatic projection irrespective of location.
Enucleation undertaken slightly later results in an abolition of the uncrossed projection from the temporal retina
of the remaining eye, leaving only that from more central
regions. When the course of these axons is traced at the
chiasm, many are seen to stop in regions lateral to the
chiasmatic midline (156). Hence, the effect of monocular
enucleation on the chiasm is progressively more severe
the earlier the procedure is undertaken, with only those
uncrossed cells that have already traversed the chiasm
before enucleation surviving to form an ipsilateral projection.
If such midline interactions are critical for normal
chiasm development, what happens in animals in which
fibers from each eye destined for different hemispheres
remain separate, with uncrossed cells restricted laterally?
In marsupials where the uncrossed projection is confined
laterally at all stages during development (56), enucleation has no effect on chiasmatic pathways irrespective of
the time it is undertaken. The uncrossed projection from
the remaining eye does not change in magnitude even if
the enucleation is undertaken before the formation of the
normal uncrossed projection from the temporal retina
(155). This is in sharp contrast to the results of similar
experiments in rodents and ferrets (20, 44). These results
reveal that the different fiber patterns found in adult
animals with crossed and uncrossed fibers either mixed
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
V. MATURE STRUCTURE AND DEVELOPMENT
IN NONMAMMALIAN VERTEBRATES
Many nonmammalian vertebrates have highly developed visual systems with substantial ganglion cell populations. Furthermore, because uncrossed pathways exist
Physiol Rev • VOL
in members of all vertebrate classes (170), many of these
animals are likely to have complex chiasms. As with
mammals, there have been few substantial studies of the
nonmammalian chiasm where cells giving rise to different
hemispheric projections have been traced through this
region. Those studies that have been undertaken have
mainly been focused on three animal types: frog (mainly
Xenopus laevis), bird (mainly the chick), and fish. Only
the first two will be considered, since the fish chiasm is
qualitatively distinct, in that in many fish the chiasm does
not exist as recognized in other animals. Rather, the optic
nerves lap over one another and become the optic tracts,
without fusing (117, 163).
A. Amphibians
The frog retinofugal pathway has been studied in
some detail, mainly because it is a classic animal model
used in studies of the development of the retino-tectal
system. Unfortunately, it does not possess a sophisticated
visual system, but it does have a clear partial pattern of
decussation. Cells have been described in the frog Xenopus laevis that give rise to the uncrossed chiasmatic
pathway to the thalamus. The cells that give rise to this
projection are large multipolar and confined to the temporal retina. At the optic nerve head they occupy a relatively central position. Behind the eye they regroup
around the circumference of the nerve. At this location
there are pigmented processes and an increase in nerve
diameter. Through the majority of the nerves length, uncrossed fibers remain located around the circumference.
They reorganize in the intracranial segment and adopt a
ventral location. At the point where the nerves meet,
uncrossed fibers turn directly into the optic tract without
approaching the chiasmatic midline (138, 154).
In Rana pipiens, uncrossed cells have been described following unilateral tracer injections into the tectum rather than into the thalamus (143). Uncrossed cells
were found in all retinal regions in this species and appeared to have a more diverse morphology than those
identified in Xenopus. The different retinal location of
these cells is probably due to differences in their projection, with those in Xenopus projecting to the thalamus
and those in Rana projecting to the tectum. No attempt
has been made to trace their pathway through the chiasm
in Rana.
As in the retinofugal pathway of some mammals,
there is evidence that changes in fiber order within both
projections are associated with changes in glial architecture. This is particularly true of the change in fiber order
just in front of the chiasm where fibers initiate a shift in
organization toward the pattern found in the optic tract
(154). When chiasmatic pathways are traced during development, newly growing axons can be found through
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
(75). Hence, there are no significant spatial differences in
the organization of the optic nerve of the albino compared
with that found in normally pigmented animals.
Evidence strongly suggests that the albino abnormality is related to a temporal disruption in development. It is
known that there is a disruption in the center to periphery
pattern of maturation in the albino retina (174). There is a
clear delay in the center to periphery gradient in cell
production in the ganglion cell layer, which is not obvious
very early in development but becomes increasingly more
marked toward the end of the period of ganglion cell
production (71). Also, there is a delay in the development
of some of the terminal projections in central structures
of hypopigmented animals (9). Recently, it has been
shown that cells in the developing albino retina may not
exit the cell cycle at appropriate times but are delayed by
the absence of dopa, a melanin precursor normally
present in the RPE that is known to be a cell cycle
regulator (1, 72).
As in some rodents and carnivores, uncrossed cells
are generated before those from similar eccentricities that
project across the midline; the probability of a cell projecting ipsilaterally declines with time (6, 36). If there is a
delay in patterns of ganglion cell production, it is conceivable that it might increase the probability of a cell projecting contralaterally, resulting in an aberrant crossed
projection.
During development there are two uncrossed projections. The first arises from dorso-central retina but is lost
later in development. The second arises from the temporal retina and is produced after that arising centrally.
From the earliest stage the uncrossed projection arising
from the temporal retina is abnormally small. However,
the initial uncrossed projection from central retina is
normal in albinos (19). This reinforces the idea that the
problems associated with albinism are focused later in
development rather than earlier. But it is not clear how
the delay results in the systematic shift in the naso-temporal division found in these albinos.
The data from albinos point strongly to there being a
temporal disruption in the form of a delay in ganglion cell
production in these animals, with cells leaving the cell
cycle at inappropriate points, resulting in abnormal patterns of projection through the chiasm. This reinforces
the notion that any mechanism proposed to explain chiasm development must be viewed within a dynamic temporal framework.
1409
1410
GLEN JEFFERY
B. Birds
A common feature of the bird chiasm is that it is
formed by a series of interdigitated fingers that represent
Physiol Rev • VOL
grouped optic fascicles from each eye that alternate
across the midline (117, 163). Although this feature has
been seen in numerous bird species, it has only been
systematically examined in the chick. Here, the fascicles
are separated from each other by blood vessels and connective tissues. There appears to be little or no change in
fiber order within or between fascicles along the nerve
and through the chiasm (40). The total number of fascicles crossing the midline is ⬃34, although there is considerable variability in this number (38). A similar, although less marked, pattern of interdigitation can be seen
in marsupials and tree shrews (80, 81). In tree shrews the
fascicles are also segregated by connective tissue (81).
That these common features exist in such diverse animal
types says little about their relationship to one another,
but it does highlight the large diversity in chiasmatic
architecture.
During development, early optic axons enter the bird
chiasm along the outer limiting membrane and pass between radially oriented processes of neuroepithelial cells
(39). As more fibers accumulate in this region, the majority of growth cones, but not all, are identified in the
ventral-most fascicles. This distribution gradient becomes
more marked with progressive development so that the
chiasm appears to develop predominantly from the pial
surface.
It has commonly been assumed that birds do not
have an uncrossed chiasmatic pathway. However, a transitory projection can be found in the developing chick,
and careful analysis has revealed that this does not regress completely. A small uncrossed projection can be
identified in restricted regions of the thalamus and the
pretectum at maturity (111). Unfortunately, the retinal
origin of this projection in the mature animal is not
known, nor is its chiasmatic course. But during development optic axons can be identified entering the ipsilateral
optic tract at the dorsal margin of individual fascicles.
These fibers appear to arise from fascicles that are mainly
composed of fibers destined to cross the midline (101).
The chick is not alone in having an uncrossed projection
to the thalamus and pretectum. A similar pattern of projection has been identified in the quail. In this study a
number of different tracer methods were used to reveal
the projection, but it could only be identified with the
most sensitive of these, which is consistent with the
projection being very small (175).
VI. CONCLUSION
Our understanding of the organization of chiasm and
the factors that sculpt its development has been restricted
by the very limited range of animal models that have been
used to analyze this structure. It is increasingly clear that
there is no such thing as the mammalian chiasm; rather,
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
the most ventral regions of the proximal nerve. Initially,
the chiasm is formed from a loose meshwork of glial
processes and optic and nonoptic axons. With development, axons that have grown through the chiasm are
displaced dorsally and caudally to form the deeper layers
of the chiasm. There is no clear glial segregation between
new and old fibers (182).
Interestingly, the development of the uncrossed projection in Xenopus is regulated by thyroxine, the hormone
that is responsible for metamorphic induction in this animal (63). Small injections of thyroxine into the eye can
induce the precocious development of an uncrossed pathway through the chiasm in an animal before metamorphosis. Hence, an uncrossed projection can be induced in one
eye while that from the other has still to develop. The
development of this projection can also be retarded by
blocking thyroxine systemically. Furthermore, it is then
possible to induce development of an uncrossed pathway
at will following withdrawal of systemic thyroxine blockade. These results reveal that interactions between fibers
from both eyes at the chiasm are not necessary for normal
chiasm development in Xenopus. These data also support
the notion that in this animal there is no specific temporal
window for the development of the uncrossed pathway
(64 – 66). However, there are some qualifications to the
above manipulations, in that it appears that it is not
possible to induce an uncrossed projection very early in
development, only in a time window just before metamorphosis (106).
Ephrins and Ephs are ligand and receptor molecules
shown to be involved in key developmental processes
including topographic ordering of retinal projections (60).
Studies undertaken in Xenopus have shown that EphB
expressing retinal ganglion cells appear at metamorphosis in a subpopulation of temporal retinal ganglion cells,
which have an uncrossed pathway. When such cells are
grafted to younger embryos, these cells project across the
midline, implying that an appropriate chiasmatic signal is
absent at this early stage. Ephrin-B is expressed at the
chiasm of metamorphic animals, but not before. When it
is expressed prematurely in the embryonic chiasm it induces a precocious uncrossed pathway from EphB expressing ganglion cells (106). Interestingly, the authors of
this study also state that they could not detect Ephrin-B in
the chiasm of fish or birds, but did detect weak label at
E13.5 and more marked label at E16.5 in the mouse,
consistent with the time at which uncrossed fibers grow
through the chiasmatic region (25). However, the role of
Ephrin-B in the mammalian chiasm has still to be explored.
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
I am indebted to B. Mulholland and members of my laboratory who have read versions of this review and helped disentangle my misconceptions and my English.
Address for reprint requests and other correspondence: G.
Jeffery, University College London, Institute of Ophthalmology,
Bath Street, London EC1V 9EL, UK (E-mail: g.jeffery
@ucl.ac.uk).
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
REFERENCES
1. AKEO K, TANAKA Y, AND OKISAKA S. A comparison between melanotic
and amelanotic retinal pigment epithelial cells in vitro concerning
the effects of L-dopa and oxygen on cell cycle. Pigment Cell Res 7:
145–151, 1994.
2. ALLODI S, CAVALCANTE LA, HOKOC JN, AND BERNARDES RF. Genesis of
neurons of the retinal ganglion cell layer in the opossum. Anat
Embryol 185: 489 – 499, 1992.
3. APKARIAN P, BOUR LJ, BARTH PG, WENNIGER-PRICK L, AND VERBEETEN
B JR. Non-decussating retinal-fugal fiber syndrome. An inborn achiasmatic malformation associated with visuotopic misrouting, visual evoked potential ipsilateral asymmetry and nystagmus. Brain
118: 1195–1216, 1995.
4. BAKER GE. Prechiasmatic reordering of fibre diameter classes in the
retinofugal pathway of the ferret. Eur J Neurosci 2: 24 –33, 1990.
5. BAKER GE AND JEFFERY G. Distribution of uncrossed axons along the
course of the optic nerve and chiasm of rodents. J Comp Neurol
289: 455– 461, 1989.
6. BAKER GE AND REESE BE. Chiasmatic course of temporal retinal
axons in the developing ferret. J Comp Neurol 330: 95–104, 1993.
7. BAKER GE AND STRYKER MP. Retinofugal fibres change conduction
velocity and diameter between the optic nerve and tract in ferrets.
Nature 344: 342–345, 1990.
8. BARTSCH U, KIRCHHOFF F, AND SCHACHNER M. Immunohistological
localization of the adhesion molecules L1, N-CAM, and MAG in the
Physiol Rev • VOL
26.
27.
28.
29.
30.
31.
32.
33.
34.
developing and adult optic nerve of mice. J Comp Neurol 284:
451– 462, 1989.
BERMAN NE AND PAYNE BR. An exuberant retinocollicular pathway
in Siamese kittens: effects of competition and abnormal activity on
its maturation. Brain Res 354: 197–209, 1985.
BIRD AC. Field loss due to lesions at the anterior angle of the
chiasm. Proc R Soc Med 65: 519 –520, 1972.
BLACK JA, WAXMAN SG, RANSOM BR, AND FELICIANO MD. A quantitative study of developing axons and glia following altered gliogenesis in rat optic nerve. Brain Res 380: 122–135, 1986.
BODENSTEIN L AND SIDMAN RL. Growth and development of the
mouse retinal pigment epithelium. I. Cell and tissue morphometrics
and topography of mitotic activity. Dev Biol 121: 192–204, 1987.
BODENSTEIN L AND SIDMAN RL. Growth and development of the
mouse retinal pigment epithelium. II. Cell patterning in experimental chimaeras and mosaics. Dev Biol 121: 205–219, 1987.
BOVOLENTA P AND MASON C. Growth cone morphology varies with
position in the developing mouse visual pathway from retina to first
targets. J Neurosci 7: 1447–1460, 1987.
BOYCOTT BB AND WASSLE H. The morphological types of ganglion
cells of the domestic cat’s retina. J Physiol (Lond) 240: 397– 419,
1974.
BRITTIS PA AND SILVER J. Multiple factors govern intraretinal axon
guidance: a time-lapse study. Mol Cell Neurosci 6: 413– 432, 1995.
BROUWER B AND ZEEMAN WPC. The projection of the retina in the
primary optic neuron in monkeys. Brain 49: 1–35, 1926.
BUTLER P. Studies in Vertebrate Evolution. New York: Winchester,
1972.
CHAN S, BAKER G, AND GUILLERY R. Differential action of the albino
mutation on two components of the rat’s uncrossed retinofugal
pathway. J Comp Neurol 336: 362–377, 1993.
CHAN SO AND GUILLERY RW. Developmental changes produced in the
retinofugal pathways of rats and ferrets by early monocular enucleations: the effects of age and the differences between normal and
albino animals. J Neurosci 13: 5277–5293, 1993.
CHAN SO AND GUILLERY RW. Changes in fiber order in the optic nerve
and tract of rat embryos. J Comp Neurol 344: 20 –32, 1994.
CHIEN CB, ROSENTHAL DE, HARRIS WA, AND HOLT CE. Navigational
errors made by growth cones without filopodia in the embryonic
Xenopus brain. Neuron 11: 237–251, 1993.
CHUNG KY, TAYLOR JS, SHUM DK, AND CHAN SO. Axon routing at the
optic chiasm after enzymatic removal of chondroitin sulfate in
mouse embryos. Development 127: 2673–2683, 2000.
COLELLO SJ AND COLEMAN LA. Changing course of growing axons in
the optic chiasm of the mouse. J Comp Neurol 379: 495–514, 1997.
COLELLO RJ AND GUILLERY RW. The early development of retinal
ganglion cells with uncrossed axons in the mouse: retinal position
and axonal course. Development 108: 515–523, 1990.
COLELLO RJ AND GUILLERY RW. Observations on the early development of the optic nerve and tract of the mouse. J Comp Neurol 317:
357–378, 1992.
COLELLO SJ AND GUILLERY RW. The changing pattern of fibre bundles
that pass through the optic chiasm of mice. Eur J Neurosci 10:
3653–3663, 1998.
COLELLO RJ AND JEFFERY G. Evaluation of the influence of optic stalk
melanin on the chiasmatic pathways in the developing rodent
visual system. J Comp Neurol 305: 304 –312, 1991.
COOPER ML AND PETTIGREW JD. The decussation of the retinothalamic pathway in the cat, with a note on the major meridians of the
cat’s eye. J Comp Neurol 187: 285–311, 1979.
COWEY A AND PERRY VH. The projection of the temporal retina in
rats, studied by retrograde transport of horseradish peroxidase.
Exp Brain Res 35: 457– 464, 1979.
COWEY A AND PERRY VH. The projection of the fovea to the superior
colliculus in rhesus monkeys. Neuroscience 5: 53– 61, 1980.
DAY AL. Aneurysms of the ophthalmic segment: a clinical and
anatomical analysis. J Neurosurg 72: 677– 691, 1990.
DEAN G AND USHER CH. Experimental research on the course of the
optic fibres. Brain 26: 524 –542, 1903.
DODD J, MORTON SB, KARAGOGEOS D, YAMAMOTO M, AND JESSELL TM.
Spatial regulation of axonal glycoprotein expression on subsets of
embryonic spinal neurons. Neuron 1: 105–116, 1988.
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
there is a diverse series of structures that are put together
in different ways in different animals. Although significant
advances have been made in the fields of cellular and
molecular biology in relation to chiasm development,
these have only been undertaken primarily on mice,
whose chiasm is probably not representative of the majority of other mammals including humans.
Different laboratories perceive chiasm formation in
terms of the methods they employ. However, irrespective
of the animal type considered, a myriad of different factors probably play a role in chiasm development, and the
different methods employed to analyze its maturation
whether histological, molecular, or cellular reveal only
different facets of a complex interactive process. Even in
the mouse there has been little effort to try to understand
how these different features interact and too great a
tendency to interpret chiasm formation in terms of a
single mechanism. Little effort has been made to see the
dynamic nature of this region. The axis of fiber ingrowth
rotates by almost 45° between the first and last ganglion
cell entering the chiasm. Early axons navigate through a
loose cellular environment, while late fibers are packed in
a much tighter framework with older cohorts. It is unlikely that the nature of navigational decisions in pathway
selection remain the same over these periods within any
individual animal model.
1411
1412
GLEN JEFFERY
Physiol Rev • VOL
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
artefact of monocular enucleation. Trans Am Ophthalmol Soc 95:
579 – 609, 1997.
HORTON JC, GREENWOOD MM, AND HUBEL DH. Non-retinotopic arrangement of fibres in cat optic nerve. Nature 282: 720 –722, 1979.
HOSKINS SG AND GROBSTEIN P. Induction of the ipsilateral retinothalamic projection in Xenopus laevis by thyroxine. Nature 307: 730 –
733, 1984.
HOSKINS SG AND GROBSTEIN P. Development of the ipsilateral retinothalamic projection in the frog Xenopus laevis. I. Retinal distribution of ipsilaterally projecting cells in normal and experimentally
manipulated frogs. J Neurosci 5: 911–919, 1985.
HOSKINS SG AND GROBSTEIN P. Development of the ipsilateral retinothalamic projection in the frog Xenopus laevis. II. Ingrowth of
optic nerve fibers and production of ipsilaterally projecting retinal
ganglion cells. J Neurosci 5: 920 –929, 1985.
HOSKINS SG AND GROBSTEIN P. Development of the ipsilateral retinothalamic projection in the frog Xenopus laevis. III. The role of
thyroxine. J Neurosci 5: 930 –940, 1985.
HOYT WF AND LUIS O. Visual fibre anatomy in the infrageniculate
pathway of the primate. Arch Ophthalmol 68: 64 –106, 1962.
HOYT WF AND LUIS O. The primate optic chiasm. Details of visual
fibre organization studied by silver impregnation techniques. Arch
Ophthalmol 70: 69 – 85, 1963.
HUBEL DH AND WIESEL TN. Receptive fields of the optic nerve fibres
in the spider monkey. J Physiol (Lond) 155: 385–398, 1960.
HUGHES A. The topography of vision in mammals of contrasting life
style: comparative optics and retinal organization. In Handbook of
Sensory Physiology. Berlin: Springer-Verlag, 1977, vol. VII/5, p.
615–737.
ILIA M AND JEFFERY G. Delayed neurogenesis in the albino retina:
evidence of a role for melanin in regulating the pace of cell generation. Dev Brain Res 95: 176 –183, 1996.
ILIA M AND JEFFERY G. Retinal mitosis is regulated by dopa, a
melanin precursor that may influence the time at which cells exit
the cell cycle: analysis of patterns of cell production in pigmented
and albino retinae. J Comp Neurol 405: 394 – 405, 1999.
ILLING RB. Axonal bifurcation of cat retinal ganglion cells as demonstrated by retrograde double labelling with fluorescent dyes.
Neurosci Lett 19: 125–130, 1980.
JEFFERY G. Retinal ganglion cell death and terminal field retraction
in the developing rodent visual system. Dev Brain Res 315: 81–96,
1984.
JEFFERY G. Distribution and trajectory of uncrossed axons in the
optic nerves of pigmented and albino rats. J Comp Neurol 289:
462– 466, 1989.
JEFFERY G. Distribution of uncrossed and crossed retinofugal axons
in the cat optic nerve and their relationship to patterns of fasciculation. Vis Neurosci 5: 99 –104, 1990.
JEFFERY G. The albino retina: an abnormality that provides insight
into normal retinal development. Trends Neurosci 20: 165–169,
1997.
JEFFERY G, COWEY A, AND KUYPERS HG. Bifurcating retinal ganglion
cell axons in the rat, demonstrated by retrograde double labelling.
Exp Brain Res 44: 34 – 40, 1981.
JEFFERY G, DARLING K, AND WHITMORE A. Melanin and the regulation
of mammalian photoreceptor topography. Eur J Neurosci 6: 657–
667, 1994.
JEFFERY G AND HARMAN AM. Distinctive pattern of organization in
the retinofugal pathway of a marsupial. II. Optic chiasm. J Comp
Neurol 325: 57– 67, 1992.
JEFFERY G, HARMAN A, AND FLUGGE G. First evidence of diversity in
eutherian chiasmatic architecture: tree shrews, like marsupials,
have spatially segregated crossed and uncrossed chiasmatic pathways. J Comp Neurol 390: 183–193, 1998.
JEFFERY G, SHARP C, MALITSCHEK B, SALT TE, KUHN R, AND KNOPFEL T.
Cellular localisation of metabotropic glutamate receptors in the
mammalian optic nerve: a mechanism for axon-glia communication. Brain Res 741: 75– 81, 1996.
JEFFERY G AND WILLIAMS A. Is abnormal retinal development in
albinism only a mammalian problem? Normality of a hypopigmented avian retina. Exp Brain Res 100: 47–57, 1994.
JESSELL TM. Adhesion molecules and the hierarchy of neural development. Neuron 1: 3–13, 1988.
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
35. DONOVAN A. The nerve fibre composition of the cat optic nerve. J
Anat 101: 1–11, 1967.
36. DRÄGER UC. Birth dates of retinal ganglion cells giving rise to the
crossed and uncrossed optic projections in the mouse. Proc R Soc
Lond B Biol Sci 224: 57–77, 1985.
37. DRÄGER UC AND OLSEN JF. Origins of crossed and uncrossed retinal
projections in pigmented and albino mice. J Comp Neurol 191:
383– 412, 1980.
38. DRENHAUS U AND RAGER G. Organization of the optic chiasm in the
hatched chick. Anat Rec 234: 605– 617, 1992.
39. DRENHAUS U AND RAGER G. Formation of alternating tiers in the
optic chiasm of the chick embryo. Anat Rec 240: 555–571, 1994.
40. EHRLICH D AND MARK R. The course of axons of retinal ganglion cells
within the optic nerve and tract of the chick (Gallus gallus).
J Comp Neurol 223: 583–591, 1984.
41. ERSKINE L, WILLIAMS SE, BROSE K, KIDD T, RACHEL RA, GOODMAN CS,
TESSIER-LAVIGNE M, AND MASON CA. Retinal ganglion cell axon guidance in the mouse optic chiasm: expression and function of Robos
and Slits. J Neurosci 20: 4975– 4982, 2000.
42. ESTEVE JV AND JEFFERY G. Reduced retinal deficits in an albino
mammal with a cone rich retina: a study of the ganglion cell layer
at the area centralis of pigmented and albino grey squirrels. Vision
Res 38: 937–940, 1998.
43. FUKUDA Y, SAWAI H, WATANABE M, WAKAKUWA K, AND MORIGIWA K.
Nasotemporal overlap of crossed and uncrossed retinal ganglion
cell projections in the Japanese monkey (Macaca fuscata). J Neurosci 9: 2353–2373, 1989.
44. GODEMENT P, SALAUN J, AND METIN C. Fate of uncrossed retinal
projections following early or late prenatal monocular enucleation
in the mouse. J Comp Neurol 255: 97–109, 1987.
45. GODEMENT P, WANG LC, AND MASON CA. Retinal axon divergence in
the optic chiasm: dynamics of growth cone behavior at the midline.
J Neurosci 14: 7024 –7039, 1994.
46. GREINER JV AND WEIDMAN TA. Histogenesis of the cat retina. Exp
Eye Res 30: 439 – 453, 1980.
47. GRUSS P AND WALTHER C. Pax in development. Cell 69: 719 –722,
1992.
48. GUILLERY R, JEFFERY G, AND SAUNDERS N. Visual abnormalities in
albino wallabies: a brief note. J Comp Neurol 403: 33–38, 1999.
49. GUILLERY RW. Neural abnormalities of albinos. Trends Neurosci 9:
364 –367, 1986.
50. GUILLERY RW. Early monocular enucleations in fetal ferrets produce a decrease of uncrossed and an increase of crossed retinofugal components: a possible model for the albino abnormality. J
Anat 164: 73– 84, 1989.
51. GUILLERY RW, POLLEY EH, AND TORREALBA F. The arrangement of
axons according to fiber diameter in the optic tract of the cat.
J Neurosci 2: 714 –721, 1982.
52. GUILLERY RW AND WALSH C. Changing glial organization relates to
changing fiber order in the developing optic nerve of ferrets.
J Comp Neurol 265: 203–217, 1987.
53. HALDER G, CALLAERTS P, AND GEHRING WJ. Induction of ectopic eyes
by targeted expression of the eyeless gene in Drosophila. Science
267: 1788 –1792, 1995.
54. HARMAN AM AND BEAZLEY LD. Generation of retinal cells in the
wallaby Setonix brachyurus (Quokka). Neuroscience 28: 219 –232,
1989.
55. HARMAN AM AND JEFFERY G. Distinctive pattern of organization in
the retinofugal pathway of a marsupial. I. Retina and optic nerve.
J Comp Neurol 325: 47–56, 1992.
56. HARMAN AM AND JEFFERY G. Development of the chiasm of a marsupial, the quokka wallaby. J Comp Neurol 359: 507–521, 1995.
57. HENDERSON Z. Distribution of ganglion cells in the retina of adult
pigmented ferret. Brain Res 358: 221–228, 1985.
58. HOGAN D AND WILLIAMS RW. Analysis of the retinas and optic nerves
of achiasmatic Belgian sheepdogs. J Comp Neurol 352: 367–380,
1995.
59. HOLDER GE. Chiasmal and retrochiasmal lesions. In: Principals and
Practice of Clinical Electrophysiology, edited by Heckenlively JR
and Arden GB. St Louis, MO: Mosby Year Book, 1991.
60. HOLDER N AND KLEIN R. Eph receptors and ephrins: effectors of
morphogenesis. Development 126: 2033–2044, 1999.
61. HORTON JC. Wilbrand’s knee of the primate optic chiasm is an
STRUCTURE AND DEVELOPMENT OF THE OPTIC CHIASM
Physiol Rev • VOL
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
microscopic analysis of synaptic development in Macaca monkey
retina as detected by immunocytochemical labeling for the synaptic vesicle protein, SV2. J Comp Neurol 339: 535–558, 1994.
O’LEARY DM, GERFEN CR, AND COWAN WM. The development and
restriction of the ipsilateral retinofugal projection in the chick.
Brain Res 312: 93–109, 1983.
PEICHL L, OTT H, AND BOYCOTT BB. Alpha ganglion cells in mammalian retinae. Proc R Soc Lond B Biol Sci 231: 169 –197, 1987.
PERRY VH AND COWEY A. The morphological correlates of X- and
Y-like retinal ganglion cells in the retina of monkeys. Exp Brain
Res 43: 226 –228, 1981.
PERRY VH, HENDERSON Z, AND LINDEN R. Postnatal changes in retinal
ganglion cell and optic axon populations in the pigmented rat.
J Comp Neurol 219: 356 –368, 1983.
PETTIGREW JD. Flying primates? Megabats have the advanced pathway from eye to midbrain. Science 231: 1304 –1306, 1986.
PETTIGREW JD, JAMIESON BG, ROBSON SK, HALL LS, MCANALLY KI, AND
COOPER HM. Phylogenetic relations between microbats, megabats
and primates (Mammalia: Chiroptera and Primates). Philos Trans
R Soc Lond B Biol Sci 325: 489 –559, 1989.
POLYAK S. The Vertebrate Visual System. Chicago, IL: Univ. of
Chicago Press, 1957.
PROVIS JM AND WATSON CR. The distribution of ipsilaterally and
contralaterally projecting ganglion cells in the retina of the pigmented rabbit. Exp Brain Res 44: 82–92, 1981.
QUINN J, WEST J, AND HILL R. Multiple functions for Pax 6 in mouse
eye and nasal development. Genes Dev 10: 435– 446, 1996.
RAPAPORT DH, FLETCHER JT, LAVAIL MM, AND RAKIC P. Genesis of
neurons in the retinal ganglion cell layer of the monkey. J Comp
Neurol 322: 577–588, 1992.
RAPAPORT DH AND STONE J. The site of commencement of maturation in mammalian retina: observations in the cat. Brain Res 281:
273–279, 1982.
REESE BE. The distribution of axons according to diameter in the
optic nerve and optic tract of the rat. Neuroscience 22: 1015–1024,
1987.
REESE BE AND BAKER GE. The course of fibre diameter classes
through the chiasmatic region in the ferret. Eur J Neurosci 2:
34 – 49, 1990.
REESE BE AND BAKER GE. Changes in fiber organization within the
chiasmatic region of mammals. Vis Neurosci 9: 527–533, 1992.
REESE BE AND COLELLO RJ. Neurogenesis in the retinal ganglion cell
layer of the rat. Neuroscience 46: 419 – 429, 1992.
REESE BE AND COWEY A. Large retinal ganglion cells in the rat: their
distribution and laterality of projection. Exp Brain Res 61: 375–385,
1986.
REESE BE AND COWEY A. Fibre organization of the monkey’s optic
tract. I. Segregation of functionally distinct optic axons. J Comp
Neurol 295: 385– 400, 1990.
REESE BE AND HO KY. Axon diameter distributions across the
monkey’s optic nerve. Neuroscience 27: 205–214, 1988.
REESE BE, JOHNSON PT, AND BAKER GE. Maturational gradients in the
retina of the ferret. J Comp Neurol 375: 252–273, 1996.
REESE B, JOHNSON PT, HOCKING DR, AND BOLLES AB. Chronotopic
fibre reordering and the distribution of cell adhesion and extracellular matrix molecules in the optic pathway of fetal ferrets. J Comp
Neurol 379: 1–17, 1997.
REESE BE, MAYNARD TM, AND HOCKING DR. Glial domains and axonal
reordering in the chiasmatic region of the developing ferret.
J Comp Neurol 349: 303–324, 1994.
REESE BE, THOMPSON WF, AND PEDUZZI JD. Birthdates of neurons in
the retinal ganglion cell layer of the ferret. J Comp Neurol 341:
464 – 475, 1994.
REICHARDT LF, BOSSY B, DE CURTIS I, NEUGEBAUER KM, VENSTROM K,
AND SRETAVAN D. Adhesive interactions that regulate development
of the retina and primary visual projection. Cold Spring Harb
Symp Quant Biol 57: 419 – 429, 1992.
ROBINSON SR. Ontogeny of the area centralis in the cat. J Comp
Neurol 255: 50 – 67, 1987.
SANYANUSIN P, SCHIMMENTI LA, MCNOE LA, WARD TA, PIERPONT ME,
SULLIVAN MJ, DOBYNS WB, AND ECCLES MR. Mutation of the PAX2
gene in a family with optic nerve colobomas, renal anomalies and
vesicoureteral reflux. Nat Genet 9: 358 –364, 1995.
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
85. KAAS JH, GUILLERY RW, AND ALLMAN JM. Some principles of organization in the dorsal lateral geniculate nucleus. Brain Behav Evol 6:
253–299, 1972.
86. KATER S AND REHDER V. The sensory-motor role of growth cone
filopodia. Curr Opin Neurobiol 5: 68 –74, 1995.
87. KAUFMAN M. The Atlas of Mouse Development. San Diego, CA:
Academic, 1992.
88. KIDD T, BROSE K, MITCHELL KJ, FETTER RD, TESSIER-LAVIGNE M,
GOODMAN CS, AND TEAR G. Roundabout controls axon crossing of
the CNS midline and defines a novel subfamily of evolutionarily
conserved guidance receptors. Cell 92: 205–215, 1998.
89. KIRK DL, LEVICK WR, CLELAND BG, AND WASSLE H. Crossed and
uncrossed representation of the visual field by brisk-sustained and
brisk-transient cat retinal ganglion cells. Vision Res 16: 225–231,
1976.
90. KRIEGLER S AND CHUI S. Calcium signalling of glial cells among
mammalian axons. J Neurosci 13: 4229 – 4245, 1993.
91. KRUGER K, TAM AS, LU C, AND SRETAVAN DW. Retinal ganglion cell
axon progression from the optic chiasm to initiate optic tract
development requires cell autonomous function of GAP-43. J Neurosci 18: 5692–5705, 1998.
92. LA VAIL MM, RAPAPORT DH, AND RAKIC P. Cytogenesis in the monkey
retina. J Comp Neurol 309: 86 –114, 1991.
93. LEVENTHAL AG, AULT SJ, AND VITEK DJ. The nasotemporal division in
primate retina: the neural bases of macular sparing and splitting.
Science 240: 66 – 67, 1988.
94. MACDONALD R, SCHOLES J, STRAHLE U, BRENNAN C, HOLDER N, BRAND
M, AND WILSON SW. The Pax protein Noi is required for commissural
axon pathway formation in the rostral forebrain. Development 124:
2397–2408, 1997.
95. MAGGS A AND SCHOLES J. Glial domains and nerve fiber patterns in
the fish retinotectal pathway. J Neurosci 6: 424 – 438, 1986.
96. MANN I. The Development of the Eye (3rd ed.). London: British
Medical Association, 1964.
97. MARCUS RC, BLAZESKI R, GODEMENT P, AND MASON CA. Retinal axon
divergence in the optic chiasm: uncrossed axons diverge from
crossed axons within a midline glial specialization. J Neurosci 15:
3716 –3729, 1995.
98. MARCUS RC AND MASON CA. The first retinal axon growth in the
mouse optic chiasm: axon patterning and the cellular environment.
J Neurosci 15: 6389 – 6402, 1995.
99. MARCUS RC, SHIMAMURA K, SRETAVAN D, LAI E, RUBENSTEIN JL, AND
MASON CA. Domains of regulatory gene expression and the developing optic chiasm: correspondence with retinal axon paths and
candidate signal cells. J Comp Neurol 403: 346 –358, 1999.
100. MARCUS RC, WANG LC, AND MASON CA. Retinal axon divergence in
the optic chiasm: midline cells are unaffected by the albino mutation. Development 122: 859 – 868, 1996.
101. MCLOON SC AND LUND RD. Transient retinofugal pathways in the
developing chick. Exp Brain Res 45: 277–284, 1982.
102. MEISSIREL C AND CHALUPA LM. Organization of pioneer retinal axons
within the optic tract of the rhesus monkey. Proc Natl Acad Sci
USA 91: 3906 –3910, 1994.
103. NAITO J. Course of retinogeniculate projection fibers in the cat optic
nerve. J Comp Neurol 251: 376 –387, 1986.
104. NAITO J. Retinogeniculate projection fibers in the monkey optic
nerve: a demonstration of the fiber pathways by retrograde axonal
transport of WGA-HRP. J Comp Neurol 284: 174 –186, 1989.
105. NAITO J. Retinogeniculate projection fibers in the monkey optic
chiasm: a demonstration of the fiber arrangement by means of
wheat germ agglutinin conjugated to horseradish peroxidase.
J Comp Neurol 346: 559 –571, 1994.
106. NAKAGAWA S, BRENAN C, JOHNSON KG, SHEWAN D, HARRIS WA, AND
HOLT CE. Ephrin-B regulates the ipsilateral routing of retinal axons
at the optic chiasm. Neuron 25: 599 – 610, 2000.
107. NEWTON I. Opticks: Or a Treaties of the Reflexions, Refractions,
Inflections and Colours of Light. New York: McGraw-Hill, 1931.
108. NICLOU SP, JIA L, AND RAPER JA. Slit2 is a repellent for retinal
ganglion cell axons. J Neurosci 20: 4962– 4974, 2000.
109. NG AYK AND STONE J. The optic nerve of the cat: appearance and
loss of axons during normal development. Dev Brain Res 5: 263–
271, 1982.
110. OKADA M, ERICKSON A, AND HENDRICKSON A. Light and electron
1413
1414
GLEN JEFFERY
Physiol Rev • VOL
159. TORREALBA F, GUILLERY RW, EYSEL U, POLLEY EH, AND MASON CA.
Studies of retinal representations within the cat’s optic tract.
J Comp Neurol 211: 377–396, 1982.
160. TORRES M, GOMEZ-PARDO E, AND GRUSS P. Pax2 contributes to inner
ear patterning and optic nerve trajectory. Development 122: 3381–
3391, 1996.
161. VAN VACTOR D. Adhesion and signaling in axonal fasciculation. Curr
Opin Neurobiol 8: 80 – 86, 1998.
162. VITEK DJ, SCHALL JD, AND LEVENTHAL AG. Morphology, central projections, and dendritic field orientation of retinal ganglion cells in
the ferret. J Comp Neurol 241: 1–11, 1985.
163. WALLS G. The Vertebrate Retina and Its Adaptie Radiation. Bloomfield Hills, MI: Cranbrook, 1942.
164. WALSH C. Age-related fiber order in the ferret’s optic nerve and
optic chiasm. J Neurosci 6: 1635–1642, 1986.
165. WALSH C AND GUILLERY RW. Age-related fiber order in the optic tract
of the ferret. J Neurosci 5: 3061–3069, 1985.
166. WALSH C AND POLLEY EH. The topography of ganglion cell production in the cat’s retina. J Neurosci 5: 741–750, 1985.
167. WALSH C, POLLEY EH, HICKEY TL, AND GUILLERY RW. Generation of
cat retinal ganglion cells in relation to central pathways. Nature
302: 611– 614, 1983.
168. WALTHER C, GUENET JL, SIMON D, DEUTSCH U, JOSTES B, GOULDING
MD, PLACHOV D, BALLING R, AND GRUSS P. Pax: a murine multigene
family of paired box-containing genes. Genomics 11: 424 – 434,
1991.
169. WANG LC, DANI J, GODEMENT P, MARCUS RC, AND MASON CA. Crossed
and uncrossed retinal axons respond differently to cells of the optic
chiasm midline in vitro. Neuron 15: 1349 –1364, 1995.
170. WARD R, REPERANT J, HERGUETA S, MICELI D, AND LEMIRE M. Ipsilateral visual projections in non-eutherian species: random variation
in the central nervous system? Brain Res Rev 20: 155–170, 1995.
171. WÄSSLE H. Morphological types and central projections of ganglion
cells in the cat retina. Prog Ret Res 1: 125–152, 1982.
172. WÄSSLE H AND BOYCOTT BB. Functional architecture of the mammalian retina. Physiol Rev 71: 447– 480, 1991.
173. WÄSSLE H AND ILLING RB. The retinal projection to the superior
colliculus in the cat: a quantitative study with HRP. J Comp Neurol
190: 333–356, 1980.
174. WEBSTER MJ AND ROWE MH. Disruption of developmental timing in
the albino rat retina. J Comp Neurol 307: 460 – 474, 1991.
175. WEIDNER C, REPERANT J, MICELI D, HABY M, AND RIO JP. An anatomical study of ipsilateral retinal projections in the quail using radioautographic, horseradish peroxidase, fluorescence and degeneration techniques. Brain Res 340: 99 –108, 1985.
176. WILBRAND HL AND SAENGER A. Die Neurologie des Auges. Ein Handbuch fur Nerven und Augenarzte. Wiesbaden: Bergman, 1904.
177. WILLIAMS RW, BASTIANI MJ, LIA B, AND CHALUPA LM. Growth cones,
dying axons, and developmental fluctuations in the fibre population
of the cat’s optic nerve. J Comp Neurol 246: 32– 69, 1986.
178. WILLIAMS RW, BORODKIN M, AND RAKIC P. Growth cone distribution
patterns in the optic nerve of fetal monkeys: implications for
mechanisms of axon guidance. J Neurosci 11: 1081–1094, 1991.
179. WILLIAMS RW AND CHALUPA LM. An analysis of axon caliber within
the optic nerve of the cat: evidence of size groupings and regional
organization. J Neurosci 3: 1554 –1564, 1983.
180. WILLIAMS RW, HOGAN D, AND GARRAGHTY PE. Target recognition and
visual maps in the thalamus of achiasmatic dogs. Nature 367:
637– 639, 1994.
181. WILLIAMS RW AND RAKIC P. Dispersion of growing axons within the
optic nerve of the embryonic monkey. Proc Natl Acad Sci USA 82:
3906 –3910, 1985.
182. WILSON MA, TAYLOR JSH, AND GAZE RM. A developmental and ultrastructural study of the optic chiasma in Xenopus. Development 102:
537–553, 1988.
183. ZHANG HY AND HOFFMANN KP. Retinal projections to the pretectum,
accessory optic system and superior colliculus in pigmented and
albino ferrets. Eur J Neurosci 5: 486 –500, 1993.
81 • OCTOBER 2001 •
www.prv.org
Downloaded from http://physrev.physiology.org/ by 10.220.32.247 on July 4, 2017
136. SARNAT HB AND NETSKY G. Evolution of the Nervous System. Oxford, UK: Oxford Univ. Press, 1981.
137. SCHAMBRA U, LAUDER J, AND SILVER J. Atlas of the Prenatal Mouse
Brain. San Diego, CA: Academic, 1992.
138. SCHUTTE M AND HOSKINS SG. Ipsilaterally projecting retinal ganglion
cells in Xenopus laevis: an HRP study. J Comp Neurol 331: 482–
494, 1993.
139. SENGELAUB DR, DOLAN RP, AND FINLAY BL. Cell generation, death,
and retinal growth in the development of the hamster retinal ganglion cell layer. J Comp Neurol 246: 527–543, 1986.
140. SHIRASAKI R, MIRZAYAN C, TESSIER-LAVIGNE M, AND MURAKAMI F. Guidance of circumferentially growing axons by netrin-dependent and
-independent floor plate chemotropism in the vertebrate brain.
Neuron 17: 1079 –1088, 1996.
141. SILVER J AND RUTISHAUSER U. Guidance of optic axons in vivo by a
preformed adhesive pathway on neuroepithelial endfeet. Dev Biol
106: 485– 499, 1984.
142. SILVER J AND SAPIRO J. Axonal guidance during development of the
optic nerve: the role of pigmented epithelia and other extrinsic
factors. J Comp Neurol 202: 521–538, 1981.
143. SINGMAN EL AND SCALIA F. Quantitative study of the tectally projecting retinal ganglion cells in the adult frog. I. The size of the
contralateral and ipsilateral projections. J Comp Neurol 302: 792–
809, 1990.
144. SKOFF RP. Gliogenesis in rat optic nerve: astrocytes are generated
in a single wave before oligodendrocytes. Dev Biol 139: 149 –168,
1990.
145. SRETAVAN DW, FENG L, PURE E, AND REICHARDT LF. Embryonic
neurons of the developing optic chiasm express L1 and CD44, cell
surface molecules with opposing effects on retinal axon growth.
Neuron 12: 957–975, 1994.
146. SRETAVAN DW AND KRUGER K. Randomizated retinal ganglion cell
axon routing at the optic chiasm of GAP-43-deficient mice: association with midline recrossing and lack of normal ipsilateral axon
turning. J Neurosci 18: 10502–10513, 1998.
147. SRETAVAN DW, PURE E, SIEGEL MW, AND REICHARDT LF. Disruption of
retinal axon ingrowth by ablation of embryonic mouse optic chiasm neurons. Science 269: 98 –101, 1995.
148. SRETAVAN DW AND REICHARDT LF. Time-lapse video analysis of retinal ganglion cell axon pathfinding at the mammalian optic chiasm:
growth cone guidance using intrinsic chiasm cues. Neuron 10:
761–777, 1993.
149. STOECKLI ET AND LANDMESSER LT. Axonin-1, Nr-CAM, and Ng-CAM
play different roles in the in vivo guidance of chick commissural
neurons. Neuron 14: 1165–1179, 1995.
150. STOECKLI ET AND LANDMESSER LT. Axon guidance at choice points.
Curr Opin Neurobiol 8: 73–79, 1998.
151. STONE J. The number and distribution of ganglion cells in the cat’s
retina. J Comp Neurol 180: 753–772, 1978.
152. TAMADA A, SHIRASAKI R, AND MURAKAMI F. Floor plate chemoattracts
crossed axons and chemorepels uncrossed axons in the vertebrate
brain. Neuron 14: 1083–1093, 1995.
153. TAYLOR J. Mechanismus oder neue abhandl. v. d. kunstl. Zusammensetz. des menschlichen Auges. Frankfurt, 1750.
154. TAYLOR J. Fibre organization and reorganization in the retinotectal
projection of Xenopus. Development 99: 393– 410, 1987.
155. TAYLOR JS AND GUILLERY RW. Does early monocular enucleation in
a marsupial affect the surviving uncrossed retinofugal pathway? J
Anat 186: 335–342, 1995.
156. TAYLOR JS AND GUILLERY RW. Effect of a very early monocular
enucleation upon the development of the uncrossed retinofugal
pathway in ferrets. J Comp Neurol 357: 331–340, 1995.
157. THANOS S, BONHOEFFER F, AND RUTISHAUSER U. Fiber-fiber interaction
and tectal cues influence the development of the chicken retinotectal projection. Proc Natl Acad Sci USA 81: 1906 –1910, 1984.
158. THEISS P AND GRÜSSER OJ. Vision and cognition in the natural
philosophy of Albert the Great (Albertus Magnus). Doc Ophthalmol
86: 123–151, 1994.