Download Patterns of neuronal migration in the embryonic cortex

Review
TRENDS in Neurosciences Vol.27 No.7 July 2004
Patterns of neuronal migration in the
embryonic cortex
Arnold R. Kriegstein1,2 and Stephen C. Noctor1
1
Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA
Department of Pathology, and the Center for Neurobiology and Behavior, Columbia University Medical Center, New York,
NY 10032, USA
2
Real-time imaging of migrating neurons has changed
our understanding of how newborn neurons reach their
final positions in the developing cerebral cortex. The
migratory routes and modes of migration are more
diverse and complex than previously thought. The finding that cortical interneurons migrate to the cortex
from origins in the ventral telencephalon has already
markedly altered our view of cortical migration. More
recent findings have demonstrated additional nuances
in the migratory pattern and highlighted differences
between subsets of interneurons. Moreover, radial
migration of pyramidal neurons does not progress
smoothly from ventricle to cortical plate, but is instead
characterized by distinct migratory phases in which
neurons change shape and direction of movement. Integrating these findings with the molecular machinery
underlying migration will provide a more complete picture of how the cerebral cortex is assembled.
A curious feature of brain development is that, although
neurons are generated from precursor cells that line the walls
of the ventricular system deep within the brain, newborn
neurons often migrate long distances from their birthplace to
reach their final destinations. This is particularly evident in
the process of cortical development, whereby newborn
neurons must migrate to the outer surface of the developing
cortex. At early stages, when the cortical anlage is small,
these distances are short but as development proceeds the
distances that neurons must migrate becomes progressively
longer, and in the case of the primate brain can reach
distances up to 7 mm [1]. Studies of granule cell migration in
the developing cerebellum have provided insights into some
of the mechanisms of neuronal migration [2–4]. Recently,
with the application of molecular and genetic approaches to
the study of migration disorders in humans and in mutant
mice, many key gene products have been discovered that are
involved in neuronal migration [2,5–7]. Given the interactive
nature of the process of migration, it is not surprising that
these molecules include receptors, transcription factors,
adhesion molecules, extracellular matrix proteins, diffusible
and intracellular signaling molecules, and components of
associated signaling cascades. The focus of the current
review, however, is to describe recent advances in
Corresponding author: Arnold R. Kriegstein ([email protected]).
Available online 20 May 2004
understanding the patterns of neuronal migration in the
developing cerebral cortex. Studies based largely on realtime imaging of migrating neurons in situ in both rodent and
primate cortex have contributed significantly to a more
complete description of the routes that neurons take to reach
their proper positions and provide a framework into which
the molecular steps can be integrated.
Dynamics of cortical assembly
The first postmitotic cortical neurons collect in an outsidein sequence to form a transient layer termed the preplate
[8]. Subsequently-born neurons migrate into the preplate
to form a new series of layers collectively known as the
cortical plate, which thereby splits the preplate into a
superficial layer, the marginal zone, and a deeper layer,
the subplate. As additional waves of migrating neurons
arrive in the cortical plate they bypass earlier-generated
neurons to form the cortical layers in an inside-out
sequence; deeper layers are the first to form, superficial
layers the last [9]. The correlation of laminar fate with
birth order holds for all cortical neurons, including
pyramidal neurons that constitute the principle projection
neurons, and interneurons that are primarily inhibitory
local circuit neurons [10– 12]. Recent studies probing the
sites of origin and mode of migration of cortical neurons
have demonstrated that whereas cortical pyramidal
neurons are generated in the germinal zones of the dorsal
telencephalon [13 – 15], most, if not all, cortical interneurons are generated in the ventral telencephalon
[16 –19]. The latter region includes the proliferative
zones of the ganglionic eminence. Thus, cortical pyramidal
neurons can generally follow a relatively direct radial path
to their laminar position in the developing cortex, but
interneurons must travel circuitously and traverse a
greater distance (Figure 1). The migratory routes of
neurons arising in both the dorsal and ventral telencephalon have been the subject of intense study. Recent
observations, although still falling short of providing a
complete picture, indicate that migration patterns are
complex, characterized by spatially and temporally distinct changes in the direction of movement and speed of
migration for both pyramidal cells and interneurons.
Non-cortical origin of cortical interneurons
Recent studies have demonstrated that many cortical
interneurons originate in the basal ganglia primordia –
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Figure 1. Cortical interneurons derive from the ventral telencephalon and reach their final locations by migrating through specific phases. (a) Origin of interneurons in the
ventral telencephalon. Most cortical interneurons are generated in the medial ganglionic eminence (MGE) of the ventral telencephalon and migrate across the corticostriatal junction (broken line) to enter the dorsal telencephalon. (b) Phases of interneuron migration within the dorsal telencephalon. Cortical interneurons arising in the
ventral telencephalon migrate tangentially in the cortex, and then change direction to enter the cortical plate (CP) by following a radial or an oblique path. The broken line
indicates that some interneurons have been observed to descend radially into the CP and others to continue radially to deeper laminae. Abbreviations: IZ, intermediate
zone; LGE, lateral ganglionic eminence; LV, lateral ventricle; MZ, marginal zone; SVZ subventricular zone; VZ, ventricular zone.
the lateral, medial and caudal ganglionic eminences (LGE,
MGE and CGE, respectively) – and migrate tangentially
into the cerebral cortex. These include studies using dye
labeling [18], retroviral lineage analysis or chimeric mice
[19 – 21], as well as analysis of mutant mice lacking the
transcription factors Dlx or Mash 1, which are normally
expressed in the proliferative zone of the ventral telencephalon. These mice lack most cortical GABAergic
interneurons [16,22 –24]. Evidence from cell transplantation and fate-mapping experiments indicates that the
MGE is the primary source of cortical interneurons in
rodents [19,25 – 28], although cortical interneurons might
also derive from the LGE [25,29], CGE [30] and retrobulbar area [31]. Multiple classes of inhibitory neurons are
present in the cortex, and it appears that most, with the
exception of those that express calretinin, arise in the
MGE [32]. In humans, a significant number of cortical
GABAergic interneurons also appear to arise from
progenitors in the cortical subventricular zone (SVZ)
[33,34]. The exact origin of the SVZ interneuron precursors
in primates (i.e. whether they are derived from the cortical
ventricular zone (VZ) [33] or from the ventral telencephalon), and the degree to which a similar pattern might exist
in other species including rodents, is still unclear.
Tangential migration of interneurons: distinct phases
Whereas all cortical interneurons arising in the MGE
must migrate tangentially to reach the cortex, the
migration pathways used by MGE cells change through
development [25,35]. Early in rodent neurogenesis, GABAexpressing cells from the MGE migrate through the
intermediate zone (IZ) of the ganglionic eminence and
disperse to all cortical layers, whereas later-born cells
migrate through the striatal VZ and SVZ to enter the
cortex. Within the developing cortex, the initial bands of
tangentially migrating interneurons are most prominent
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in the lower IZ and SVZ and in the marginal zone (MZ) and
subplate [19,25,27,29,35,36]. Data from rodent brain also
suggest that some interneurons could derive from the
LGE. Early in neurogenesis, interneurons arising in the
LGE appear to populate the cortical preplate [18,29]. Later
in neurogenesis, LGE-derived cells migrate tangentially
through the SVZ on their way to the cortical plate [25]. A
recent study using real-time imaging of glutamate
decarboxylase 67 green fluorescent protein (Gad67-GFP)
knock-in mice to examine the migration of GABAergic
neurons has provided a potentially more accurate picture
of pathways of migration than previous studies based on
labeling with 1,10 -dioctadecyl-3,3,30 ,30 -tetramethylindocarbocyanine perchlorate (DiI) or on transplantation
strategies. The data confirm that migration of cortical
interneurons appears to occur primarily in two streams, in
the cortical MZ and the IZ – SVZ. Once in the cerebral
cortex, interneurons disperse tangentially and then
generally enter the cortical plate by turning to migrate
radially to their final positions [25,26,35– 37] (Figure 1).
Many take the most direct route by turning to enter the
cortical plate. For example, cells migrating tangentially in
the IZ – SVZ have been observed to turn and migrate
radially or obliquely to enter the cortical plate from below
[26,35,36], whereas interneurons migrating tangentially
in the MZ have been observed to turn and enter the cortical
plate from above [35,36]. Neurons migrating tangentially
have been noted to migrate more rapidly (, 50 mm h21)
[26,27,35,38,39] than neurons migrating radially
(,10 mm h21) [39 – 43]. The radial phase of interneuron
migration can be guided by radial glial fibers [33,35], but
although this is an attractive hypothesis it has yet to be
proved. The identity of the substrate used by tangentially
migrating neurons is also uncertain. Though both radial
glia and axons have been suggested to be involved, the
evidence is not compelling [33,35,37,44,45].
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TRENDS in Neurosciences Vol.27 No.7 July 2004
Many interneurons appear to take more complex routes
to reach the cortical plate. For example, some interneurons
migrate tangentially through the IZ – SVZ, then turn and
migrate radially through the cortical plate to enter the MZ
[36]. It has been suggested that they might then disperse
in the MZ before turning again to enter the cortical plate to
reach their final positions [36]. Interestingly, a proportion
of tangentially migrating neurons from all cortical layers
were observed to undergo ventricle-directed migration to
the VZ in slice-culture preparations [37]. Upon reaching
the ventricle, these cells paused briefly and reversed
direction to migrate radially into the cortical plate [37].
The majority of these cells were interneurons, and dye
labeling of the ganglionic eminence confirmed that they
originated in the basal forebrain. Ventricle-directed
migration was observed with increasing frequency at
later stages of corticogenesis. That some tangentially
migrating neurons should contact the ventricle and then
ascend into the cortical plate has led to speculation that
neurons might obtain laminar address information
through epigenetic signals in the cortical VZ [37,46].
Another possibility is that interneuron subtypes might
migrate along specific routes. For example, ventricledirected migration could occur for only a particular class of
interneuron. This hypothesis should be testable.
A variety of factors have been shown to participate in
the guidance of tangentially migrating interneurons into
the cerebral cortex. These factors include semaphorin –
neuropilins [47,48], cell adhesion molecules such as polysialylated neural cell adhesion molecule (PSA-NCAM),
neuregulins [49], and the slit and robo families of attractant and repellent molecules [50,51]. The action of these
factors could combine to create permissive corridors to
guide interneurons during tangential migration [52].
Modes of radial migration in the developing neocortex
Cortical neurons that migrate radially into the cortical plate
are thought to do so through one of two possible modes:
translocation or locomotion. Translocating cells possess a
relatively long pia-directed process that has a stable attachment with the pial surface or marginal zone [53–56]. The
translocating cell moves its nucleus radially within this fixed
process to reach an appropriate position in the cortex. By
contrast, locomoting cells are freely migrating cells that
have a relatively ‘short’ leading process (, 100 – 200 mm)
[42,56,57] and that migrate in the radial direction along
radial glial guides [3,58,59]. Because cortical neurons
derive from radial glial cells [60 – 64], it has been suggested
that a newborn neuron could inherit the radial glial fiber
at mitosis and then translocate [62]. Alternatively, a newborn neuron could extend a radial process to the pia before
beginning translocation.
Magini made the first observations to link cells with
radial processes to neuronal migration. He noted varicosities on the radial fibers in embryonic cortex (‘like the
grains of a rosary’) and suspected that these were neuronal
nuclei migrating along single radial cell processes [65].
Berry and Rogers also studied Golgi-stained tissue and
concluded that radial fibers were multinucleated and
proposed that neuronal nuclei translocated within the pial
fibers [66]. It is now known that radial glia are not
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multinucleated, but varicosities in the radial glial fiber or
multiple neurons migrating along a single glial fiber can
produce a multinucleated appearance. Morest examined
Golgi-stained developing opossum cortex and suggested
that translocation might be the major mode of migration
for cortical neurons [53]. However, the Golgi method fails
to label freely migrating neurons that are known to be
present during embryonic ages (e.g. interneurons), and it
is often difficult to phenotype cells based on morphology
alone. Brittis and colleagues described cells at early stages
of cortical development that were immunopositive for a
monoclonal antibody (2G12) that labels phosphorylated
growth-associated-protein 43 (GAP-43), which is expressed
in neurons [67] and mitotic precursor cells [68,69]. They
described cells with nuclei at the ventricular surface and
fibers coursing to the pia that were interpreted as
translocating neurons. However, these cells resemble radial
glial cells in M-phase of the cell cycle that are now known to
retain their radial fibers during division [62,70] and to
express a variety of phosphorylated proteins, including
phosphorylated vimentin [71], phosphorylated mitogenactivated protein kinase (phospho-MAPK), and phosphorylated c-Jun (A.R. Kriegstein and T.A. Weissman, unpublished). These cells were not co-labeled with neuron-specific
markers, so it is possible that they were M-phase radial glia
rather than translocating neurons. Nadarajah and colleagues performed real-time imaging of migrating cells in
slice cultures from mice at embryonic day (E)13 and E14 and
distinguished translocating cells from locomoting cells [56].
However, other real-time imaging experiments performed in
the E14 mouse have provided contradictory results reporting that the majority of neurons migrate either through
translocation [62] or through non-translocation modes [41].
These contrasting findings could be due to differences in celllabeling techniques, experimental procedures or conditions,
as well as in cell-type identification methods.
Translocation has been proposed to be the major mode of
migration during the earliest stages of cortical development [46,72]. This model implies that the early-generated
preplate neurons or deep layer neurons begin migration
from the VZ with a leading process fixed at the pial surface.
This might be particularly true during early cortical
development when the length of the leading process of a
migrating neuron approximates the width of the developing cortical mantle. The early-born neurons would thus be
restricted to migrating radially to the cortical plate. In this
way the cortical VZ would provide a ‘protomap’ for the
location of the early-generated preplate neurons [59,73].
This attractive model could explain why in some neuronal
migration disorders the early-forming preplate develops
normally but the later-generated cortical plate, when
neurons rely more on locomotion, becomes disordered [74].
Real-time imaging experiments performed during the
early stages of preplate generation are needed to provide
a more complete picture of the roles of locomotion and
translocation in cortical development.
Pattern of radial migration in the cortex: distinct phases
of locomotion
It has long been suspected that cortical pyramidal
neurons arise from the proliferative zones of the dorsal
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TRENDS in Neurosciences Vol.27 No.7 July 2004
telencephalon [75]. This has been confirmed in recent
experiments including those based on cortical explants
isolated from ventral telencephalon [13], fate-mapping
studies of transgenic mice [14], and transcription factor
expression in pyramidal neurons [15]. Recent studies
using time-lapse imaging in slice cultures have demonstrated that neurons generated in the cortical proliferative
zones at later stages of development pass through a series
of distinct migrational stages characterized by abrupt
changes in cell shape, direction of movement, and speed
of migration as they move to the cortical plate [41,42]
(Figure 2). These observations have led to a scheme that
divides radial migration into four distinct phases [42]. In
phase one, neurons generated at the ventricular surface
move radially away from the ventricle to the SVZ. In phase
two, they pause in the IZ – SVZ for as long as 24 h and
become multipolar. Previous studies based on birth-dating
techniques had also noted that migrating neurons paused
or ‘sojourned’ in the lower IZ –SVZ during radial migration
[76]. Time-lapse imaging of cells in phase two demonstrates that multipolar cells are highly dynamic, extending and retracting processes and moving within the SVZ.
Neurons do not appear to be tightly adhered to radial glial
guide fibers at this stage, and are capable of moving
tangentially [41]. In some cases cells have been observed to
move several cell bodies laterally only to return to their
original locations [42]. Many, but not all, neurons pass
through a third phase, during which they extend a process
towards the ventricle and often also translocate the cell
body toward the ventricle [42]. Upon reaching the
ventricle, neurons enter phase four of migration. The
neurons reverse polarity and extend a pia-directed leading
process, take on the bipolar morphology of migrating
neurons, and begin radial migration to the cortical plate
[42]. Some neurons are observed to begin radial migration
following a migratory pause in the SVZ but without
retrograde motion toward the ventricle. According to the
proposed scheme, these neurons do not pass through phase
three, but instead progress directly from phase two to four
(Figure 2). This indicates that subsets of excitatory
neurons undergo distinct routes of migration to the
cortical plate. Phase four migration to the cortical plate
appears to be gliophilic and neurons take on the migratory
characteristics of radially guided locomoting cells [42].
Transitions between phases of migration
Transitions between phases of migration might involve
environmental signals and depend upon specific intracellular events. Moreover, specific neuronal migration
disorders might involve failure of neurons to transition
from one phase to another [7]. For example, the condition
known as doublecortex (subcortical band heterotopia) could
involve arrest of neurons in phase two of migration. Recent
observations using in utero electroporation of VZ precursor
cells with small-interfering RNA (siRNA) of doublecortin
protein resulted in premature arrest of migrating multipolar
neurons in the IZ–SVZ [77]. This observation is consistent
with neurons failing to make the transition from phase two
to phase three of migration. Doublecortin protein has a role
in microtubule stabilization and has been proposed to have
roles in nuclear translocation or process elongation [78–81].
Because dysfunction of doublecortin is thought to produce
disruptions in microtubule organization and/or dynamics,
these observations suggest that the initial movement of cells
from the ventricle to the SVZ and the multipolar ‘sojourn’
phase might be relatively independent of doublecortin
function. However, directed radial migration towards the
cortical plate or ventricle might depend on doublecortindependent microtubule reorganization.
Birthdate-dependent laminar fate for both pyramidal
neurons and interneurons
The cortex develops in an inside-out manner, with
early-generated neurons occupying deep layers and
MZ
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IZ
SVZ
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Figure 2. Cortical pyramidal neurons undergo distinct phases of locomotion migration. Phase one involves radial movement of pyramidal neurons (dark green) from the
site of origin at the ventricular surface to the subventricular zone (SVZ). In phase two, cells become multipolar and pause their migration in the lower intermediate zone (IZ)
and subventricular zone (SVZ). Some neurons undergo phase three, which is characterized by retrograde motion toward the ventricle. Phase four is the final radial
migration to the cortical plate (CP), guided by radial glial fibers. Radial glia (light green) remain mitotic, undergo interkinetic nuclear migration, and generate additional
daughter cells (grey). Abbreviations: MZ, marginal zone; R, radial glial cell; VZ, ventricular zone.
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late-generated neurons migrating beyond the earlygenerated neurons to occupy more superficial layers [9].
Birthdate labeling experiments confirm that cortical
interneurons and pyramidal cells both follow the insideout layering sequence [10 –12]. An exception appears to be
the somatostatin-expressing interneurons that appear to
be born early [82]. The realization that GABAergic
neurons destined for the cortex arise in the ventral
telencephalon and migrate long distances tangentially
raises the question of how these cells come to occupy the
same cortical layers as radially migrating pyramidal cells
born at the same time. The ‘sojourning’ of pyramidal
neurons in the SVZ during phase two might delay their
migration sufficiently for isochronically-generated GABAergic cells to complete their tangential migration into the
dorsal cortex, allowing both cell types to reach the same
layer at the same time (Figure 3).
The convergence of the migratory routes of at least some
interneurons and pyramidal neurons at the ventricle could
provide a mechanism to coordinate their migration. It has
been suggested that the ventricle-directed migration of
interneurons might serve to direct interneurons to the
appropriate cortical layer [37]. Could the pyramidal
neurons that undergo similar ventricle-directed migration
do so for a similar purpose? Heterochronic transplant
experiments involving ferret neocortex suggest that the
laminar fate of pyramidal neurons arising in the cortical
VZ is indeed determined by local epigenetic factors but, at
least for early-generated neurons, commitment to laminar
fate is determined before the final cell division [83,84]. If
this is so, then environmental signals during migration
cannot play a role in layer-determination for these cells.
More recently, the laminar fate determination of interneurons has been examined. Heterochronic transplant
experiments were performed using MGE donor cells
transplanted into a cortical VZ host environment [85].
Transplantation of MGE interneuron progenitors indicated that late-born interneurons could change their
laminar fate when transplanted to a younger environment, suggesting that extrinsic signals can influence
laminar fate decisions for these interneurons. But when
early-born interneurons that had undergone S-phase in
the young donor environment were transplanted into an
older host, they maintained the lower-layer fate of the
donor. Therefore, at least for later born interneurons, local
epigenetic signals in the MGE might help determine
laminar fate. It is thus possible that both interneurons and
pyramidal cells undergo ventricle-directed migration to
acquire laminar fate determining signals. Alternatively,
because late-born cortical progenitors are restricted to
populating upper layers only [83,86], whereas late-born
interneurons appear uncommitted [85], interneurons
could contact specific pyramidal neurons during the
ventricular phase of migration, and simply follow them
to the appropriate cortical layer. It is also possible that
contact of GABAergic and glutamatergic neurons in the VZ
could help establish the characteristic local circuit
connections [87].
Tangential dispersion of cortical-derived neurons could
occur in phase two
Cortical neurons arise from radial glia [60– 64] and
daughter neurons often migrate along the parental fiber
[60]. However, this is not the rule, and migrating neurons
also travel along parallel adjacent paths, presumably
using adjacent radial glial fiber guides [42,88]. In rodents,
clonally related neurons become tangentially dispersed,
particularly in the upper layers, as reflected by the conical
appearance of columns of related cells in chimeric mouse
models [20]. Using retroviral lineage analysis with a
MZ
CP
IZ
SVZ
R
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R
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Figure 3. Migratory patterns of interneurons and pyramidal neurons converge in the dorsal cortex. This scheme depicts the apparent convergence of the migratory patterns
of interneurons (red) and pyramidal cell movements (dark green) in the cortex. Subsets of both cell types display ventricle-directed migration followed by radial movement
to the cortical plate (CP). Interneurons might migrate radially along unrelated, adjacent radial glial cells (grey) to reach the cortical plate. Abbreviations: IZ, intermediate
zone; MZ, marginal zone; R, radial glial cell; SVZ, subventricular zone; VZ, ventricular zone.
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TRENDS in Neurosciences Vol.27 No.7 July 2004
library of genetically tagged retroviruses, Walsh and
Cepko demonstrated that clones originating from a single
progenitor could disperse progressively over time [89].
Although most remained relatively clustered, others were
dispersed by distances of $2 mm [89] and could be
distributed across widespread functional areas [90]. The
recent findings that cortical interneurons from the
ganglionic eminence migrate tangentially in the dorsal
cortex indicate that these cells could contribute to the
tangential dispersion of clonal cells. Even so, the relative
contributions of interneurons and pyramidal cells to the
patterns of clonal dispersion have not yet been determined, and other mechanisms might also account for
dispersion of clonal cells in the dorsal cortex. For example,
evidence indicates that tangential dispersion might occur
among progenitor cells in the ventricular zone [91,92]
and/or postmitotic neurons in the dorsal cortex [89,93].
Time-lapse imaging of migratory behavior in slice cultures
has confirmed tangential dispersion of cortical neurons
[39]. It has been demonstrated that the majority of
newborn neurons move radially to the SVZ (in phase
one) [38,42]; thus, it is likely that tangential dispersion of
postmitotic neurons occurs during later phases. Neurons
could disperse tangentially in phase two of migration,
because this is a phase characterized by dynamic
‘exploratory’-type cell movements and a phase where
tangential movements have been observed in slice-culture
preparations [41,42]. Subsequently, cells migrating tangentially in phase two could account for the migrating
postmitotic neurons observed in the VZ, SVZ and lower
IZ [38,39]. It is possible that, in addition to postmitotic
neurons, some tangentially dispersed cells might also be
intermediate precursor cells [42]. In the first case, this
would account for single dispersed neurons; in the second,
for periodic related cell clusters [89,93]. It is also possible
that cells in phase four might be able to follow tangential or
oblique migration paths or to jump between radial glial
fibers and become dispersed, but it is unlikely that neurons
would become widely distributed during this phase of
radial-glia-guided migration.
Lower IZ–SVZ might favor tangential migration of both
interneurons and pyramidal cells
Tangential migration occurs at all depths of the cortex, but
particularly high percentages of tangentially migrating
cells have been observed in the SVZ and lower IZ by most
observers [19,27,29,36,45,94]. The neocortical SVZ and
lower IZ have thus been proposed to serve as a main
corridor for the tangential migration of cortical interneurons [27,36]. Interestingly, the lower IZ – SVZ also
represents a decision point for radially migrating neurons,
which pause in this region and either resume radial
migration or take a tangential path [41,42,76,94]. The
IZ – SVZ is also a zone where many neurons become
branched and dynamically extend and retract processes.
This is the case for pyramidal neurons in the multipolar
phase (phase two) of migration [41,42], and also for
interneurons migrating into the cortical IZ – SVZ from
the striatum [26,72]. Possibly the lower IZ –SVZ is a region
rich in morphogenetic signals that influence the behavior
of both interneurons and pyramidal cells.
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397
Concluding remarks
Patterns of neuronal migration during cortical development appear more complicated than once thought. Cortical
interneurons take a predominantly tangential path to
reach the cortex and travel relatively long distances,
whereas pyramidal cells take a predominantly radial path
and reach the cortex more directly. Detailed studies of the
dynamic movements of both cell types have revealed that
cells undergo distinct phases in migration. The transitions
between these phases might signal changes in the mechanisms of cell guidance or motility. Moreover, it is clear that
there are heterogeneous patterns of migration for both
interneurons and pyramidal cells. This observation suggests that specific cell types take distinct migration paths.
Unraveling the diversity of migrational strategies displayed by cortical neurons could allow a more complete
understanding of the mechanisms that contribute to
neuronal migration disorders.
Acknowledgements
We thank Stewart Anderson and Tamily Weismann for helpful comments
on the manuscript. This work was supported by the NIH and a grant from
the Lieber Center (ARK).
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