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Mechanisms of Development 105 (2001) 47±56
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Neuronal migration
Catherine Lambert de Rouvroit, Andre M. Gof®net*
Neurobiology Unit, University of Namur Medical School, 61 Rue de Bruxelles, B5000 Namur, Belgium
Received 7 December 2000; accepted 22 January 2001
Abstract
Like other motile cells, neurons migrate in three schematic steps, namely leading edge extension, nuclear translocation or nucleokinesis,
and retraction of the trailing process. In addition, neurons are ordered into architectonic patterns at the end of migration. Leading edge
extension can proceed at the extremity of the axon, by growth cone formation, or from the dendrites, by formation of dendritic tips. Among
both categories of leading edges, variation seems to be related to the rate of extension of the leading process. Leading edge extension is
directed by micro®lament polymerization following integration of extracellular cues and is regulated by Rho-type small GTPases. In
humans, mutations of ®lamin, an actin-associated protein, result in heterotopic neurons, probably due to defective leading edge extension.
The second event in neuron migration is nucleokinesis, a process which is critically dependent on the microtubule network, as shown in many
cell types, from slime molds to vertebrates. In humans, mutations in the PAFAH1B1 gene (more commonly called LIS1) or in the
doublecortin (DCX) gene result in type 1 lissencephalies that are most probably due to defective nucleokinesis. Both the Lis1 and
doublecortin proteins interact with microtubules, and two Lis1-interacting proteins, Nudel and mammalian NudE, are components of the
dynein motor complex and of microtubule organizing centers. In mice, mutations of Cdk5 or of its activators p35 and p39 result in a migration
phenotype compatible with defective nucleokinesis, although an effect on leading edge formation is also likely. The formation of architectonic patterns at the end of migration requires the integrity of the Reelin signalling pathway. Other known components of the pathway include
members of the lipoprotein receptor family, the intracellular adaptor Dab1, and possibly integrin alpha 3 beta 1. Defective Reelin leads to
poor lamination and, in humans, to a lissencephaly phenotype different from type 1 lissencephaly. Although the action of Reelin is unknown,
it may trigger some recognition-adhesion among target neurons. Finally, pattern formation requires the integrity of the external limiting
membrane, defects of which lead to overmigration of neurons in meninges and to human type 2 lissencephaly. q 2001 Elsevier Science
Ireland Ltd. All rights reserved.
Keywords: Lissencephaly; PAFAH1B1; Lis1; Doublecortin; Cdk5; Nudel; p35; p39; Reeler; Reelin; Dab1; VLDLR; ApoER2; Filamin; Limiting membrane;
Integrin
1. Introduction
Cell migration occurs widely at all stages of embryonic
development, yet it is nowhere more evident than during
mammalian brain development. Like other cells, neurons
migrate following three schematic steps (Fig. 1). First, the
cell extends leading edges, preceded by ®lopodia and lamellipodia that explore the micro-environment. Leading edge
extension proceeds following the integration of attractive
and repulsive signals generated at the plasma membrane.
This integration, thought to be regulated by small GTPases
switches of the Rho family (Luo, 2000) in¯uences the
peripheral micro®lament network by regulating actin polymerization. Secondly, cell migration requires that the
nucleus moves into the leading process, a step referred to
* Corresponding author. Tel.: 132-81-724-277; fax: 132-81-724-280.
E-mail address: andre.gof®[email protected] (A.M. Gof®net).
as `nucleokinesis' following Morris (1998; and references
therein). Nucleokinesis is distinct and differentially regulated from leading edge extension, and critically dependent
on the microtubule cytoskeleton. The third event in cell
migration is retraction of the trailing process, an aspect of
neuronal migration that is scarcely addressed in the literature. Unlike other cells, neurons form de®ned cell patterns
(architectonics) at the end of migration, and this may be
considered a `fourth step' of neuronal migration. Pattern
formation is controlled by the Reelin signaling pathway
and requires the integrity of the `limiting membrane',
consisting of the sheet of glial end-feet and basal lamina
that separate the brain from the meninges (Fig. 2).
2. Leading edge extension
Neurons extend different leading edges, only some of
which are followed by nucleokinesis and neuronal migra-
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C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
Fig. 1. Schematic view of a migrating neuron. Leading edge extension occurs by polymerization of the actin meshwork, while nucleokinesis is dependent on
microtubules organized with their minus end radiating from the microtubule organizing center (yellow dot). The retraction of the trailing process is generally
not considered important.
tion. By birth, neurons are epithelial bipolar cells (Bradke
and Dotti, 2000). As a ®rst approximation, the axonal
domain derives from the luminal, ventricular pole of the
neuroepithelial precursor, whereas the somatodendritic
membrane derives from the basolateral domain. Although
common mechanisms probably regulate axonal and dendritic extension, this fundamental distinction between axonal
and dendritic membrane domains is likely to be re¯ected at
the level of the leading edge. Thus, a ®rst useful distinction
may be between leading edge extension at the extremity of
axons, that is growth cone formation, and at the level of
dendrites.
Axonal growth cone elongation is by far the most extensively investigated mode of process extension (reviewed in
Tessier-Lavigne and Goodman, 1996; Mueller, 1999). In
contrast, it is rarely considered in the context to neuronal
Fig. 2. Schematic illustration of normal (A) and different abnormalities of cortical development (C±E). In the normal cortex, neurons proliferate in the
ventricular zone and migrate along radial ®bers. Early postmigratory neurons settle horizontally in the marginal zone (red) and subplate (pink). Reelin
produced in the marginal zone (red neurons) helps organize postmigratory neurons into layers. Early born cortical neurons (green) are found in the depth of the
cortex and younger cells (blue) more super®cially, according to the so-called `inside-outside' gradient. When leading edge extension is defective (B) as in
familial heterotopias, neurons cannot migrate from the ventricular zones and settle locally. In case of defective nucleokinesis (C), as occurs probably in type 1
lissencephaly, initial migration is satisfactory but many cells settle at subcortical level. In the absence of Reelin signaling (D), cortical neurons (green) settle
obliquely in the cortex and displace the early contingent (red and pink) `en bloc' in the marginal zone; the next generation (blue) cannot cross the ®rst one and
the gradient is directed from outside to inside. Finally, when the limiting membrane is defective (E), as in type 2 lissencephaly, streams of neurons overmigrate
in the marginal zone and in the meninges.
C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
migration, because it is seldom followed by nucleokinesis.
For example, motoneurones send long axons to peripheral
muscles, but the cell body does not move out of the spinal
cord. In contrast, sensory neurons derived from the neural
crest extend an early axon capped by a growth cone; the
nucleus then moves into this process for some length but
stops in the dorsal root ganglion where it translocates out of
the axon, leaving the well-known T-shaped sensory neuron.
In the central nervous system (CNS), neuronal migration
following growth cone elongation is referred to as `neuro(no)philic' (Rakic, 1990); it occurs tangentially and super®cially, close to the pial surface. The best studied examples
are the subpial migration of external cerebellar granule cells
from the rhombic lip over the cerebellar cortex (Hatten,
1999) and the circumferential migration of inferior olivary
neurons from the rhombic lip around the brainstem (Bourrat
and Sotelo, 1988). In the primate telencephalon, the stream
formed by the subpial granular layer (SGL) seems to follow
a similar migration mode (Meyer et al., 2000). Although the
growth cone navigates in subpial position, it is worth pointing out that it does not come in direct contact with the basal
lamina but is separated from the mesoderm by the end-feet
of neuroepithelial-glial cells. The difference between
growth cone elongation with and without cell migration is
related to the control of nucleokinesis rather than growth
cone navigation per se. The role of netrins during migration
of pontine (Yee et al., 1999) and inferior olivary cells
(Bloch-Gallego et al., 1999) suggests that the factors that
control directional growth during neuronophilic migration
are similar to those that control growth cone steering. In
contrast to the leading process of inferior olivary neurons,
indistinguishable from an axon (Bourrat and Sotelo, 1988;
Bloch-Gallego et al., 1999), the long leading process that
precedes migrating pontine neurons lacks many classical
axonal markers, suggesting that there are intermediate
differentiation states between long leading edges and fully
differentiated axons (Yee et al., 1999).
Other modes of leading edge extension proceed at the
dendritic domain of the neuron and are morphologically
described as `dendritic growth cones or tips'. Most often,
the cell processes elongate along the radial dimension of the
neuroepithelium and radial glial cells. This has been mostly
studied in the cerebral cortex and cerebellum, and is referred
to as `gliophilic migration' (for review, see Rakic, 1990;
2000a,b). It accounts for the majority of neuronal migration
events all over the brain. The radial, gliophilic tip is elongate, closely apposed to the surface of radial cells that are
thought to provide the substrate and guide its extension.
Among the proteins implicated in neuronal-glial interactions are astrotactin (see Hatten, 1999, for review) and
integrins, particularly integrin alpha3-beta1 that seems to
mediate the interaction between the tip and substrate, at
least in the cerebral cortex (Anton et al., 1999). Apart
from this, our understanding of the determinants that govern
dendritic tip steering and elongation remains frustratingly
rudimentary. A reason may be that, contrary to axonal elon-
49
gation, migration by radial tip formation is not easily amenable to experimental analysis in vitro. It is worth pointing
out that radial neuronal migration can occur without formation of a typical dendritic tip, particularly at early developmental stages when neurons have to travel very short
distances. Recent observations suggest that, during very
early cortical development, some neurons migrate radially
without forming a leading process, simply by losing their
attachment to the ventricle and undergoing nuclear translocation (Nadarajah et al., 1999). In addition, early neurons
that migrate to the cerebral cortex do not have a bipolar but a
stellate shape, as shown long ago with the Golgi method
(e.g. Derer, 1994) and electron microscopic reconstruction
(Shoukimas and Hinds, 1978). In comparison with later
migrating cells, these stellate neurons seem to have more
than one leading process and dendritic tip; they do not
strictly follow radial cell extensions and their migration is
slow. The presence of radially migrating cells that do not
follow the classical gliophilic dendritic tip may explain the
presence of an early, well formed cortical plate in the cerebral cortex of mice de®cient in cyclin-dependent kinase 5
(Cdk5) (see below). Clearly, migration by radial, dendritic
tip formation obeys cues that are different from those that
govern neuronophilic migration. In many instances, radial
migration is orthogonal to subpial migration. Both processes
can be activated sequentially in the same cell, for example
in cerebellar granule cells, and lead to extension of axonal
and dendritic processes in different directions. An important, unresolved question concerns the mechanisms that
direct nucleokinesis either in a growing axon or in a growing
dendrite.
Until a few years ago, leading edge extension by formation of subpial axonal growth cones and radial dendritic tips
was considered to account for all cases of neuronal migration. However, important examples have been discovered
that depart from these two modes. First, as mentioned
above, radial non-gliophilic migration is observed during
early cortical development. A second case is the so-called
`chain migration' by which neurons migrate from subventricular zones in the lateral ganglionic eminences to the
olfactory bulb (and possibly other forebrain areas) by
following a glial tunnel that extends through the tissue,
mostly with a tangential orientation (Luskin, 1993; Wichterle et al., 1997; Law et al., 1999). The third example is the
migration of GABAergic neurons from the medial ganglionic eminence to the cerebral cortex (Anderson et al., 1997,
reviewed by Parnavelas, 2000). These neurons have an elongated shape with one or two prominent, horizontally elongated leading processes that extend through the intermediate
zone by following the trajectory of corticofugal axons
(Denaxa et al., 2000). Interestingly, they expressed
calcium-permeant AMPA receptors whereas corticofugal
axons are glutamatergic (MeÂtin et al., 2000). Some of
these neurons even seem to migrate towards the cortical
ventricular zone (Nadarajah et al., 2000). As far as we
know, whether the leading edges from cortical immigrants
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C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
from the ganglionic eminences correspond to axonal growth
cones or dendritic tips remains unclear. Similarly, the regulation of nuclear displacement in these cells is unknown.
Such a wide variety of leading processes presumably
re¯ects the diversity of microenvironmental cues and the
diverse signaling pathways that direct their growth. In the
face of such diversity, apart from the basic difference
between axonal and dendritic cones, it is tempting to try
and de®ne some common mechanisms. Morphological
studies suggest that the shape of a leading process re¯ects
its rate of extension, maximal for growth cones, less rapid
for tangential intraparenchymatous extension and even
slower for radial migration. In the case of axonal growth
cones, it is well known that they are larger and more prominent when the elongation rate is slow, as the growth cone
explores the environment, whereas growth cones that cap
rapidly extending axons are thin and straight.
Some observations, however, suggest that this view is
oversimpli®ed and that there are different machineries for
leading edge extension. As a ®rst example, X-linked periventricular heterotopias in humans have been linked to
mutations in ®lamin, an actin-associated protein (see Fox
et al., 1998; Fox and Walsh, 1999). This observation shows
that, like axonal growth cones, leading tip elongation
requires the contractility of actin micro®laments. Nonmuscle ®lamin is a large protein (265±280 kDa) with two
actin-binding domains linked by a long ¯exible shaft, that
cross links actin ®laments into a loose, plastic meshwork.
Filamin can bind to the intracellular domain of integrins,
caveolin-1, TNF alpha receptor, and other surface proteins,
thus providing a link between the cell surface and the actin
network. This coupling is regulated by the Ras-related small
GTPases Cdc42, Rac, Rho and RalA which all bind ®lamin.
In the case of radial neuronal migration, it is thought that
®lamin de®ciency blocks the elongation of the dendritic tip
along radial cell extensions, for example by uncoupling
integrins from micro®laments. As a result neurons cannot
leave the ventricular zone and differentiate locally into
nodular heterotopias. Interestingly, although detailed neuropathological studies are not available, it seems that this
mutation does not affect leading edge extension by growth
cone formation. Apparently, connections and even commissural tracts develop normally, and cerebellar granule cells
migrate satisfactorily. This malformation may thus de®ne a
speci®c, ®lamin-dependent mode of leading edge extension
that appears to be used mainly for radial (gliophilic migration), an idea that could be checked by careful neuropathological studies and by analysis of relevant mouse models.
Another example in which formation of different leading
edges seems to be differentially affected in Cdk5 or p35
de®cient mice (Ohshima et al., 1996; Gilmore et al., 1998;
Chae et al., 1997; Kwon and Tsai, 2000). Cdk 5 mutant mice
harbor a wide defect of radial migration all over the brain.
Subpial neuronophilic migration of cerebellar granule cells
and inferior olivary neurons also appears defective, and
there are signs of axonal degeneration. However, many
tracts appear to develop normally, initial cortical plate
formation in the cortex proceeds correctly and the tangential, intraparenchymatous migration of GABAergic neurons
from ganglionic eminence to cortex seems relatively unaffected.
3. Nucleokinesis
As mentioned above, leading edge extension is not
consistently followed by nuclear translocation. However,
it is mainly the translocation of the nucleus into the leading
process that de®nes cell migration, and the factors that regulate this process are thus of paramount importance (Book
and Morest, 1990). Two examples illustrate this point. The
®rst is again cerebellar granule cells. During tangential
subpial migration, their nuclei move in the immature
axon, forming the external granule cell layer. In response
to a signal from Purkinje cells, probably Hedgehog (Wechsler-Reya and Scott, 1999), a dendritic tip extends from the
cell body, and elongates radially along Bergmann glial cells.
The nucleus then translocates in this process and settles in
the depth of the cerebellar cortex, forming the inner granule
cell layer. In this case, the axonal growth cone and dendritic
tip are both followed by nuclear displacement, yet follow
different cues, as they elongate in orthogonal directions. A
second example is facial motoneurons. They are generated
in the ventricular zone of the fourth ventricle and send an
early axon laterally to form the facial nerve. Then they
extend a dendritic process that extends radially, probably
guided by radial cells, into which nucleokinesis proceeds.
This movement of the cell body leaves the axon behind,
resulting into the typical `hairpin' trajectory of facial
nerve known as the `genu'.
In our view, these examples illustrate a key question
about neuronal migration: What are the factors that allow
and regulate nuclear translocation into a growing immature
process? As introduced above, the term `nucleokinesis' was
proposed by Morris to describe mutations which disturb the
regular spacing of the cell nuclei in Aspergillus nidulans,
and are abbreviated `Nud' for nuclear distribution (note that,
even though both processes depend on microtubules,
`nucleokinesis' is different from `karyokinesis', which
refers to the translocation of chromosomes during mitosis).
Similar genes have been cloned in Neurospora crassa and
abbreviated `ro' for `ropy', as well as in yeast (reviewed by
Fischer, 1999). The relationships between these genes and
their mammalian orthologs are summarized in Table 1. The
similarity between NudF and mammalian PAFAH1B1/Lis1
(see below) suggests that nucleokinesis is quite independent
from leading edge extension and is an essential, hitherto
unrecognized component of neuronal migration that is
more critically dependent on microtubules. A recent review
of microtubule micromotors in neurons was published by
Goldstein and Yang (2000), and mechanisms of nuclear
positioning are discussed in Reinsch and GoÈnczy (1998).
C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
51
Table 1
Relationship between genes or proteins involved in nuclear positioning in slime molds and higher eukaryotes a
Cytoplasmic dynein components
Dynactin components
Other dynein pathway components
a
A. nidulans
N. crassa
Higher eukaryotes
NUDA
NUDI
NUDG
RO1
CD heavy chain
CD intermediate chain
CD 8-kDa light chain
P150 glued
ARP1
p70
Lis1 (PAFAH1b)
NUDC
Xenopus MP43, Nudel, mammalian NudE
NUDK
NUDF
NUDC
NUDE
RO3
RO4
RO2
RO11
Adapted from Morris (2000).
Disturbances of nucleokinesis are implicated in human
brain malformations known as type 1 lissencephalies,
which are characterized by defective migration to the cerebral cortex and are occasionally associated with disturbances of migration in other parts of the brain. In many
cases, type 1 lissencephaly has a genetic origin and two
genes have been cloned thus far, called lissencephaly 1
(PAFAH1B1 / Lis1) and doublecortin (DCX). Mutations of
LIS1 result in autosomal dominant type 1 lissencephaly
(Reiner et al., 1993; Hattori et al., 1994), whereas mutations
of doublecortin are responsible for X-linked lissencephaly
in males and for the double-cortex malformation in carrier
females (des Portes et al., 1998; Gleeson et al., 1998). In
addition, the migration defects in mice with null mutations
in the cyclin-dependent kinase 5 (Cdk5) and its cofactor p35
are reminiscent of human lissencephalies (Ohshima et al.,
1996; Chae et al., 1997) and will be summarized in this part.
Other genes implicated in type 1 lissencephalies will most
probably be isolated in the coming years.
3.1. Lis1
Homozygous null mutations of Lis1 are embryonic lethal
in mice and presumably in humans as well. Heterozygosity
for Lis1 mutations leads to type 1 lissencephaly, characterized by profuse migration defects in the brain (Reiner et al.,
1993; Hattori et al., 1994). Mice with one inactive allele
display cortical, hippocampal and olfactory bulb disorganization resulting from delayed neuronal migration by a cellautonomous neuronal pathway. Mice with further reduction
of Lis1 activity display more severe brain disorganization as
well as cerebellar defects (Hirotsune et al., 1998).
The Lis1 protein, which binds to microtubules, is also a
non-catalytic subunit of platelet-activating factor (PAF)
acetyl hydrolase 1b (PAFAH1b), an enzyme that inactivates
PAF (Hattori et al., 1994). Whether these two apparently
different roles are related remains unknown. Interestingly,
the composition of PAF acetyl hydrolase is developmentally
regulated in the brain and the catalytic subunits of PAFAH
compete with mammalian NudE (see below) for binding to
Lis1 (Manya et al., 1998; Kitagawa et al., 2000).
Since Morris ®rst noted the similarity between Lis1 and
NudF, the link between Lis1 and the microtubular cytoskeleton has been actively studied (Morris, 2000). Lis1 protein
coimmunoprecipitates with cytoplasmic dynein and components of the dynactin complex, and localizes to the cell
cortex as well as to mitotic kinetochores, both sites of
dynein binding (Smith et al., 2000). In cultured cells, overexpression of Lis1 leads to spindle misorientation and interferes with progression into mitosis, whereas interference
with Lis1 function (e.g. with anti Lis1 antibodies) disturbs
the arrangement of the metaphase plate (Faulkner et al.,
2000). Lis1 also plays a role in dendritic elaboration and
axonal transport, as shown in Drosophila and in cultured
neurons (Liu et al., 2000). These experiments suggest that
the lissencephaly that results from haploinsuf®ciency of
Lis1 may be attributed to deregulation of cell cycle progression in the ventricular zone as well as to disturbances of the
microtubule cytoskeleton that regulates nucleokinesis.
Several groups have isolated two Lis1 interacting
proteins that show similarity with the Aspergillus nidulans
NudE protein (RO11 in Neurospora, MP43 in Xenopus).
They have been named Nudel (for `NudE-like') and
rNudE, mNudE, hNudE for rat/mouse/human NudE orthologs, which we will call mammalian NudE (Kitagawa et al.,
2000; Feng et al., 2000; Niethammer et al., 2000; Sasaki et
al., 2000). Mold NudE, Nudel and mammalian NudE are all
coiled-coil proteins that have the capacity to bind Lis1 and
provide an additional link between Lis1 and dynein. Nudel
and mammalian NudE have a similar size and display 55%
identity. However, the regulation of both genes is different,
as mammalian NudE is ubiquitously expressed at early
embryonic stages, whereas Nudel expression is restricted
to brain and testes and is detected postnatally. The homology with Xenopus MP43, a protein that is phosphorylated in
a cell-cycle dependent fashion, and the fact that Nudel is an
in vitro substrate for Cdk5 suggest a role for phosphorylation in the regulation of NudE function (Niethammer et al.,
2000; Sasaki et al., 2000). The coiled-coiled regions of both
proteins interact with wild-type Lis1, but not with Lis1
proteins that harbor human lissencephaly mutations. In
Xenopus embryos, dominant negative expression of
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C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
mammalian NudE causes lamination defects in the retina,
tectum and cortex. Both proteins are located in the centrosome or microtubule organizing center (MTOC) and interact with centrosomal components including gamma-tubulin,
the dynein light chain and pericentrin (Feng et al., 2000).
Thus, several lines of evidence indicate that mammalian
NudE acts on the dynein motor complex and hence on
nuclear migration through interaction with Lis1, re¯ecting
the situation in lower organisms where NudE is located
genetically between NudF and NudA (see Table 1).
3.2. Doublecortin
Doublecortin (DCX) was characterized by positional
cloning and is responsible for the doublecortex (subcortical
laminar heterotopia) malformation in heterozygous carrier
women, and for X-linked lissencephaly in males, a phenotype similar to type 1 lissencephaly (Gleeson et al., 1998;
des Portes et al., 1998). The DCX gene encodes a 361
amino-acid protein that associates with and stabilizes microtubules (Francis et al., 1999; Gleeson et al., 1999) but shows
no similarity to any other microtubule associated protein
(Sapir et al., 1997; Taylor et al., 2000). An evolutionarily
conserved domain is tandemly repeated in the N-terminal
part of the protein and named DC repeat. Interestingly, the
majority of human missense mutations cluster in these
repeats. Each repeat alone is able to bind tubulin, but neither
is suf®cient to mediate microtubule stabilization. Some
human point mutations lead to impaired polymerization or
disruption of microtubules, thereby altering the morphology
of transfected cells. Biochemical and genetic evidence thus
point to a role for DCX in crucial microtubule-based events
in neuronal migration. However, which step of the migration process is affected in DCX mutants remains to be elucidated.
In addition to the similarity between LIS1 and DCX
mutant phenotypes, a physical interaction between Lis1
and DCX has been demonstrated both in vitro and in vivo
(Horesh et al., 1999; Caspi et al., 2000). This interaction is
not altered in DCX mutant proteins that fail to bind microtubules. As mentioned above, both LIS1 and DCX associate
with microtubules and enhance their polymerization, but the
precise mode of interaction between the three partners, and
how these events relate to the lissencephaly phenotype
remains unknown.
Sequence similarity searches identi®ed two additional
mammalian proteins with DC repeats, namely DCLK
(doublecortin-like kinase) also called KIAA0369 or
DCAMKL1, and ORP1 (retinitis pigmentosa 1). The
DCLK gene maps to human chromosome 13q12.3 where
no neurological disorders have been located so far. In addition to a N-terminal DC motif, the DCLK protein contains a
transmembrane domain and a region of similarity with
Ca 21-calmodulin-dependent protein kinases. The expression pattern of the DCLK mRNA in the embryonic brain
suggests that this gene may be involved in cortical devel-
opment (Sossey-Alaoui and Srivastava, 1999; Burgess and
Reiner, 2000; Matsumoto et al., 1999). Moreover, recent
data show that DCLK is associated with microtubules in
neuronal growth cones (Burgess and Reiner, 2000).
3.3. Cyclin-dependent kinase 5 (Cdk5) and its cofactors
p35/p39
Cdk5 was named because of its similarity to Cdc2.
However, the protein is not primarily involved in the regulation of the cell cycle. It is expressed in all postmitotic
neurons and is thought to regulate many developmental
processes during neuronal differentiation. The range of
Cdk5 substrates is not fully de®ned, but one of the main
targets is the microtubule associated protein `tau'. In addition, Nudel is also a substrate of Cdk5, and may be a link
between Cdk5/p35 and neuronal migration (Sasaki et al.,
2000; Niethammer et al., 2000). The Cdk5 kinase activity
requires the formation of a complex with one of two activators named p35 and p39. A role for these proteins in
neuronal migration was demonstrated when inactivation of
Cdk5 in mice was observed to result in profuse migration
defects (Ohshima et al., 1996). Inactivation of p35 results in
a more subtle neuronal migration disorder, probably due to
some redundancy between p35 and p39 (Chae et al., 1997).
Cdk5-de®cient mice have profuse neuronal migration
defects in the cerebral cortex, hippocampus, cerebellum,
as well as in several other parts of the CNS (Gilmore et
al., 1998; Kwon and Tsai, 2000). In addition, some axon
bundles are defective with evidence of axon swelling. Interestingly, as already pointed out above, the initial formation
of the telencephalic preplate and early cortical plate
proceeds normally, and GABAergic neurons from the ganglionic eminence seem to migrate in the cortex of Cdk5de®cient mice, suggesting that some neuron migration is
Cdk5-independent. The initial migration in the telencephalic preplate and cortical plate is short range and morphologically different from later radial migration, suggesting that
Cdk5 is needed only for long-range gliophilic migration.
Even though Cdk5 has been shown to in¯uence growth
cone formation (Nikolic et al., 1998), morphological observations of mutant mice suggest that the main action of
Cdk5/p35/p39 during neuronal migration is via the control
of nucleokinesis.
4. Patterning after migration. The Reelin signaling
pathway and type 2 lissencephalies
When neurons reach their destination, they stop migrating
and order themselves into speci®c `architectonic' patterns.
Observations in reeler mice show that the normal function
of the Reelin signaling pathway is essential for proper radial
organization and layering of postmigratory neurons at all
levels of the CNS (reviewed by Lambert de Rouvroit and
Gof®net, 1998a). Strong genetic evidence demonstrates that
Reelin, the very low density lipoprotein receptor (VLDLR),
C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
ApoE receptor type 2 (ApoER2), and the Disabled 1 (Dab1)
tyrosine kinase adaptor belong to the same pathway. Integrin alpha3 beta1 also binds Reelin and could be another
Reelin receptor (see below). Observations of type 2 lissencephaly in humans, together with some mouse mutations,
suggest that the integrity of the external limiting membrane
is also necessary for normal architectonic formation.
Reelin, the protein defective in reeler mutant mice, is a
large (about 400 kDa) glycoprotein secreted by several
neurons in the extracellular micro-environment (D'Arcangelo et al., 1995; reviewed in Lambert de Rouvroit and Gof®net, 1998b). In the embryonic cerebral cortex, hippocampus
and cerebellum, Reelin is expressed in the marginal zone and
governs the disposition and dendritic deployment of target
cells, that correspond respectively to cortical plate cells,
pyramidal cells and Purkinje cells. The response of target
cells to the Reelin signal involves the expression of
membrane receptors and intracellular signaling proteins.
Mice doubly de®cient in two lipoprotein receptors, namely
very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor type 2 (ApoER2) have a phenotype indistinguishable from reeler (Trommsdorff et al., 1999). These
proteins are expressed in Reelin target cells and bind Reelin
in a speci®c manner (Hiesberger et al., 1999; D'Arcangelo et
al., 1999). VLDLR and ApoER2 have a short cytoplasmic tail
that interacts with the tyrosine kinase adapter Dab1 (Disabled
1) via a NPXY sequence involved in lipoprotein receptormediated endocytosis. Mutations of Dab1 also generate a
reeler phenotype (Howell et al., 1997; Sheldon et al., 1997;
Ware et al., 1997). Mammalian Dab1 is expressed in the
cytoplasm of migrating cortical neurons as a 555 aminoacid protein comprising an N-terminal phosphotyrosine
binding (PTB) domain responsible for the interaction with
the lipoprotein receptors. Binding of Reelin to target cells
induces Dab1 phosphorylation in vivo and in vitro (Howell et
al., 1999). Five tyrosine phosphorylation sites have been
mapped to the Dab1 sequence. The crucial importance of
Dab1 phosphorylation in neuronal positioning is demonstrated by the generation of Dab1 `knock-in' animals in
which the ®ve tyrosine residues have been replaced by
phenylalanine. These mice display a phenotype similar to
Dab1 null mutants (Howell et al., 2000). The kinase(s)
involved in the tyrosine phosphorylation of Dab1 have not
yet been identi®ed. Dab1 was identi®ed as a Src-binding
protein in a two-hybrid screen, and is an in vitro substrate
for tyrosine kinases of the Src family. However, none of the
null mutants for Src, Abl or Fyn has a phenotype evocative of
reeler. Reelin and presumably the other partners of the pathway are present and conserved in all vertebrates, suggesting a
role in brain evolution (Bar et al., 2000).
As mentioned above, integrin alpha 3 beta1 is implicated
in the interaction between radially migrating cortical
neurons and radial glial ®bers (Anton et al., 1999). Interestingly, biochemical studies show that this integrin has many
properties of a Reelin receptor and participates in the formation of a supramolecular complex with Reelin and lipopro-
53
tein receptors (Dulabon et al., 2000). The formation of such
a complex on target cells means that alpha 3 beta 1 integrin
could be downregulated by endocytosis as soon as migrating
neurons reach a Reelin-rich area such as the border of the
marginal zone. This would detach immature neurons from
radial glial ®bers and trigger their laminar organization in
the cortical plate.
Other mechanisms are considered to explain the action of
Reelin. Reelin may provide a stop signal to migrating cells
(Pearlman and Sheppard, 1996; Pearlman et al., 1998).
Reelin cannot stop leading edge extension, as the presence
of Reelin is permissive to the deployment of dendritic tips,
for example in the marginal zone. On the other hand, cell
bodies of target cells tend to avoid Reelin-rich areas, so that
Reelin may act as a stop signal for nucleokinesis (Walsh and
Gof®net, 2000). However, recent observations (Jensen et al.,
2000) show that stopping nucleokinesis cannot explain all
actions of Reelin. A possibility, already proposed long ago
(Gof®net, 1979) is that Reelin could promote recognitionadhesion among postmigratory cells, thereby stabilizing
early architectonic patterns. These and possibly other unrecognized actions of Reelin are not mutually exclusive.
Surely, the complexity and size of the protein is compatible
with engagement of different receptors, activation of different intracellular signaling pathways, and complex phenotypic response of target cells. In humans, Reelin is expressed
during brain development (Meyer et al., 2000). Two
families with recessive lissencephaly have been shown to
carry reelin mutations (Hong et al., 2000). The human
DAB1 gene maps to chromosome 1p31 (Lambert de Rouvroit and Gof®net, 1998b); mutations of this gene are
predicted to yield a phenotype similar to mutations in reelin.
The observation that defective Reelin signaling in humans is
incompatible with normal cortical lamination and folding
further demonstrates the key importance of this pathway
for normal brain development.
4.1. The external limiting membrane
In contrast to the Reelin pathway, which seems to play an
`instructive' role during pattern formation, the role of the
limiting membrane may be viewed more as a mechanical
barrier to migration, and thus permissive to cortical lamination. The limiting membrane is composed of the end-feet of
radial neuroepithelioglial cells and the basal lamina to
which they adhere. Meningeal cells are the mesodermal
component of the border between neural and mesodermal
tissue. Defects in any of these three components is predicted
to result in radial `overmigration', with invasion of the
marginal zone and formation of neuronal streams in the
meninges. This phenotype is observed in mice de®cient in
presenilin-1 (Hartmann et al., 1999) and in alpha 6 integrins
(Georges-Labouesse et al., 1998), as well as in MARCKS
(Stumpo et al., 1995), a prominent neural substrate for
protein kinase C (although the exencephaly phenotype in
this mutant is more dramatic). These observations suggest
54
C. Lambert de Rouvroit, A.M. Gof®net / Mechanisms of Development 105 (2001) 47±56
that neuronal overmigration may result from defects in the
basal lamina but also in proteoglycans in the marginal zone
(discussed by Hartmann et al., 1999), and could also be
related to mesodermal, particularly vascular anomalies. In
humans, focal gliomeningeal heterotopias with overmigration are found sporadically, but are particularly prominent
and considered typical of type 2 lissencephalies (Friede,
1989; Barkovich and Kjos, 1992). Genetic type 2 lissencephaly is associated with Fukuyama muscular dystrophy
(FCMD), due to mutations in the so-called `fukutin' gene
of unknown function, with merosin (laminin alpha-2,
LAMA2) de®ciency, with Walker±Warburg syndrome
(WWS) and with muscle-eye-brain (MEB) disease. As far
as we know, the genes mutated in WWS and MEB have not
yet been identi®ed. Interestingly, the basal lamina of skeletal muscle ®bers is thinned and disrupted in muscle biopsies
of patients with FCMD, LAMA2 and WWS, further emphasizing the importance of the basal lamina as a key component of the limiting membrane.
4.2. Conclusion
The data summarized above show that our understanding
of neuronal migration is progressing at an accelerated pace.
As always, new knowledge leads to new questions. As a
conclusion, we would like to address some of the problems
that we tend to consider as important and timely, bearing in
mind that this is a most subjective selection. As we underscored in part one, it is important to de®ne the various
classes of neuronal leading edges on a cell biological
basis. In particular, we need to understand better the signals,
receptors and postreceptors mechanisms that govern dendritic tip extension. Second, about nucleokinesis, the role of
PAF metabolism needs to be clari®ed and the mechanism by
which microtubule direct the position of the nucleus in the
cell should be addressed. For example, is it simply the
density of microtubules that allows or prohibit nuclear translocation or, as we think, are they more subtle features? The
role on nucleokinesis of Cdk5, its cofactors and the recently
characterized Nudel and NudE remains to be determined;
human mutations for these genes are likely to be found in
families with type 1 lissencephaly. Thirdly, about endmigration event and architectonic patterns, we still do not
understand in molecular and even in descriptive terms what
Reelin really does to end the migration of neurons. The role
of the limiting membrane should be progressively unraveled
with the analysis of different mouse and human mutations.
Finally, all these themes would bene®t enormously from the
development of a reliable in vitro system in which genuine
neuronal migration and some degree of pattern formation
can be observed and studied experimentally.
Acknowledgements
We wish to thank L.-H. Tsai, C. Walsh and A. WynshawBoris for sharing prepublication data and we apologize to
colleagues whose work is not cited because of limitation
constraints. Our laboratory is supported by grants FRSM
3.4533.95, FRFC 2.4544.01, ARC 99/03-248 and the
Fondation Reine Elisabeth, all from Belgium.
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