Normal and abnormal neuronal migration in the developing cerebral cortex.

Abstract

Neuronal migration is the critical cellular process which initiates histogenesis of cerebral cortex. Migration involves a series of complex cell interactions and transformation. After completing their final mitosis, neurons migrate from the ventricular zone into the cortical plate, and then establish neuronal lamina and settle onto the outermost layer, forming an "inside-out" gradient of maturation. This process is guided by radial glial fibers, requires proper receptors, ligands, other unknown extracellular factors, and local signaling to stop neuronal migration. This process is also highly sensitive to various physical, chemical and biological agents as well as to genetic mutations. Any disturbance of the normal process may result in neuronal migration disorder. Such neuronal migration disorder is believed as major cause of both gross brain malformation and more special cerebral structural and functional abnormalities in experimental animals and in humans. An increasing number of instructive studies on experimental models and several genetic model systems of neuronal migration disorder have established the foundation of cortex formation and provided deeper insights into the genetic and molecular mechanisms underlying normal and abnormal neuronal migration.

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INTRODUCTION
The development of the mammalian cerebral cortex
is aremarkably complex process, and mainly consists
of three steps, (i) production of neuronal precursor
cells, (ii) migration to their laminar position and
(iii) finally differentiation and development of their
morphological and functional properties. The cerebral
cortex of higher vertebrates is organized in to six
layers. The layering is produced by variations in
the densities and sizes of cell bodies through the
cortical depth. All neuronal cells, with few exceptions,
are generated the surface of the embryonic cerebral
ventricles at sites far from their ultimate positions
in the adult mammalian brain (1, 2). Therefore,
neuronal migration is considered to be necessary
and an essential step in the genesis of the nervous
system, particularly in laminated brain regions
(3-6). Migration of neurons is a distinct cellular
phenomenon. By this migrating process many billions
of newly generated neural cells are addressed to
their proper position mainly in nuclear masses or
in the cerebral cortexes. General or topical loss of
control over this process generally called abnormal
neuronal migration or neuronal migration disorder.
Abnormal neuronal migration will result in either
REVIEW
Normal and abnormal neuronal migration in the developing
cerebral cortex
Xue-Zhi Sun, Sentaro Takahashi, Chun Cui
Kazuhiko Sawada
＊, Rui Zhang, Hiromi Sakata-Haga
＊,
＊and Yoshihiro Fukui
＊
Environmental and Toxicological Sciences Research Group, National Institute of Radiological
Sciences, Chiba, Japan ; and
University ofTokushimaSchool of Medicine, Tokushima, Japan
＊Department of Anatomy and Developmental Neurobiology, The
Abstract : Neuronal migration is the critical cellular process which initiates histogenesis
of cerebral cortex. Migration involves a series of complex cell interactions and transformation.
After completing their final mitosis, neurons migrate from the ventricular zone into the
cortical plate, and then establish neuronal lamina and settle onto the outermost layer,
forming an “inside-out” gradient of maturation. This process is guided by radial glial
fibers, requires proper receptors, ligands, other unknown extracellular factors, and local
signaling to stop neuronal migration. This process is also highly sensitive to various
physical, chemical and biological agents as well as to genetic mutations. Any disturbance
of the normal process may result in neuronal migration disorder. Such neuronal migration
disorder is believed as major cause of both gross brain malformation and more special
cerebral structural and functional abnormalities in experimental animals and in humans.
An increasing number of instructive studies on experimental models and several genetic
model systems of neuronal migration disorder have established the foundation of cortex
formation and provided deeper insights into the genetic and molecular mechanisms
underlying normal and abnormal neuronal migration. J . Med. Invest. 49 : 97-110, 2002
Keywords : cerebrum, ectopia, migration disorder, radial glia
Received for publication May 31, 200 ２; accepted July 10,
2002.
Address correspondence and reprint requests to Dr. Xue-Zhi
Sun, Environmental and Toxicological Sciences Research Group,
National Institute of Radiological Sciences, Anagawa 4-9-1, Inage-
ku, Chiba263-8555, Chiba, Japan and Fax : +81-43-251-4853.
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cell death or improper positioning of functional cell
groups. This in turn will result in failing connections
or improper wiring (misconnection) responsible
for functional deficiencies and epilepsy. Abnormal
migration had been linked to congnitive deficits,
mental retardation, and motor disorders (7-11).
Recently, there has been rapid progress in under-
standing the ever-surprising phenomenology of this
neuronal migration, as well as its molecular basis.
Herein we will review the normal process of neuronal
migration, disruptions in such neuronal migration
process that results several cerebral cortical disorders,
and the current understanding of the molecular
mechanisms of neuronal migration and its relation-
ship tocerebral cortical development and neuronal
migration disorder.
NORMAL NEURONAL MIGRATION IN THE
CEREBRAL CORTEX
(1) Mode of neuronal migration
Neurons that come to populate the six-layered
cerebral cortex are born deep within the developing
brain in the ventricular zone that lines the lateral
ventricle of each telencephalic hemisphere. The
ventricular zone of the telencephalon provides the
neuronal and glial stem cells (1, 2, 12-14, 17, 24).
The cortical neurons are generated in an orderly
sequence. The earliest-formed cortical neurons from
aprecocious organization referred to as the preplate.
These early born neurons from connections with
subcortical targets that are essential for development
for later connections. The preplate is subsequently
divided into two layers : an outer marginal layer
composed largely of Cajal-Retzius neurons beneath
the pial surface, and an inner layer composed of
subplate neurons-by the arrival of a later-generated
neuronal population called the cortical plate (future
cortex). Once the preplate is established, subsequent
cells which complete their final mitotic division
migrate out ofthe ventricular zone and settle between
these two layers to engage into a long migration
with radial centrifugal fashion through the inter-
mediated zone (future white matter) toward the
cortical plate where they settle and differentiate
(20). The first cells to arrive will eventually reside
in the deepest layer, layer VI. Later born cells will
migrate past the existing cells to reside in progres-
sively more superficial layers. Subsequent cohorts
of neurons repeat this mode, migrating through an
ever-thicker cortical plate, so that the newest neurons
are always at the topof the cortical plate facing the
marginal layer cells.
Neuronal migration in the neocotex takes place
for the greater part between the 8thand the 20th
weeks of gestation in humans (15) and between
embryonic day 14 (E14) and postnatal day 5 (P5)
in rats (19). The migration of young neurons is
guided from an early stage by a system of radial
glial fibers that span the width of the thickening
telecephalon (16-18). Radial glia is a specialized cell
type belonging tothe astroglial cell lineage. During
cortical development, these long bipolar cells expand
radially across the thickness of the cerebral wall.
Radial gliaare bipolar cells with one short process
extended tothe adjacent ventricular surface and a
second projecting tothe pial surface. The perikarya
of the radial glial cells are in the ventricular and
subventricular zones (21-23, 25, 26). Neurons of layer
I--the giant Cajal-Retzius neurons and layer VIb--
the lower part of layer VI are laid down as a single
neuronal network, the primordial plexiform layer
(27, 28, 33-36, 39). This primordial plexiform layer
is thought to provide a cytoskeleton for the succes-
sive neuronal migration waves as these become
sandwiched between the upper and the lower part of
the lower part of cerebral structure (Fig. 1). Neurons
migrate along the elongated radial glial fibers, which
disappear after neuronal migration has been com-
pleted, when the morphology of radial glial cells
changes intothat of astrocytes.
(2) Determining correct position of migrating neurons
within the cerebral layers
As description above, neurons are generated in
sites different from those in which they will later
reside, so the intervening neuronal migration is
necessary for this shift. On the other hand, neuronal
migration into the cortical plate must also stop at the
appropriate location. This choice point and deter-
mining this point is a key for normal cerebral
cortical development and brain functions. Some
studies have suggested that neurons completing
migration appear to require a stop signal, which
appears tobe provided by the most superficial cortical
layer or the pial membrane. This process of the
neuronal migration stop involves the detachment
fromthe radial glial fibers triggered by local signals
(Fig. 2) (29, 33, 42, 43), some of them emitted by
the Cajal-Retzius cells of the marginal zone (27, 39).
The study ofmouse mutants has led to identify some
of the molecules that regulate neuronal positioning.
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Fig. 1.
ment in three current rodent models of neuronal migration
disorder from embryonic day (E) 12, 13, 15, postnatal day
0(P 0) toadult stage. Experiment rats for nongenetic models
are treated on E 14-15with methylazoxymethanol (MAM)
or irradiation. Three models (tish mutant rat, reeler and
reeler-like mutant mouse and the prenatal irradiation-or
MAM-treated rat) show that neuronal migration disorders
can result from an abnormal neurogenesis (tish), a failure
of preplate splitting (reeler) or a lesion of radial glia cells
(X-ray, MAM). WM : white matter, SH : subcortical band
heterotopia, H : heterotopia.
Diagrammatic representation of cortical develop-
Fig. 2.
Reelin is expressed by Cajal-Retzius cell in cortical layer I
and binds the cadherin-related receptors (CNRs) and the
VLDL receptor or ApoE receptor-2, or both. CNR binding
initiates phosphorylation of a Scr family kinase, possibly
Fyn, which is considered to phosphorylate mDab-1associ-
ated with VLDLR/ApoER 2. Reelin binding to VLDLR and
ApoER2 also appears to result in phosphorylation of
mDab-1 through kinase domains in the cytoplasmic region
of the receptors. Activated mDab-1 is then though to
interact with Cdk 5, Src, and Ab 1to regulate cyotskeletal
remodeling, directly or indirectly.
Diagram to illustrate Reelin signaling pathway.
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In particular, the characterization of the Reeler
mouse mutant provided the first insights into the
process of laminar organization. The Reeler mouse
was first identified as a postnatal behavioral defect
(40), and the neuropathological studies have showed
that the cortical layering pattern is just opposite
from the normal inside to outside migrating pattern
(41, 44, 45). It has been known that Reelin is pressed
by Cajal-Retzius cells in layer I (30-32). As one of
extracellular matrix molecule, Reelin plays a role to
formaReelin’s zone tostopmigration of the earliest
generated neurons in the cerebral cortex. However,
Cajal-Retzius cells in the Reeler mice were found to
be remained at the top of the undivided preplate,
or superplate. These heterotopic Cajal-Retzius cells
are thought to be the reason to form the inverted
cortical layering in the Reeler mutant mouse (Fig. 1).
Detail description of the Reelin signaling pathway
toend cell migration will be described below.
ABNORMAL NEURONAL MIGRATION
INDUCED BY DISTINCT ENVIROMENTAL,
CHROMOSOMAL AND GENETIC CAUSES
(1) Teratogenic, physical and biological influences
The process of neuronal migration involves four
key steps : (i) neuronal migration onset, (ii) ongoing
neuronal migration, (iii) neuronal penetration into
preplate and (iv) neuronal migration completion.
One can imagine that a disruption in any step
upon which brain formation is dependent can result
in aprofound and stereotypical malformation. Various
environmental factors (teratogenic, physical and
biological factors) which can affect neuronal migra-
tion have been tested in the animal experiments.
The use of teratogenic (e.g.alcohol or cocaine) (46-
48, 55, 110), physical (e. g. irradiation, heat) (49-53)
and biological (e. g. viral infection) (54) agents has
provided animal models for studying neuronal mi-
gration disorder. These animal experiments have
involved different species and different protocols of
exposure the environmental agents to the potentially
damaging effects on the neuronal migration of the
cerebral cortex. Most of these nongenetic model
were generated by exposure of pregnant females
during the early period of migration to irradiation
or toxic substances such as the antimitotic agent
methylazoxymethanol (MAM) (56-58), cocaine(110)
or ethanol (46-48, 55). Whatever their respective
mechanisms, all these influences will lead neurons
todifferentiate in an abnormal heterotopic position.
Absence, interruption or excessive migration will
lead neurons to differentiate respectively in a
subcortical (i. e. along the ventricle), intracortical
(i. e. in the white matter or in an inappropriate
layer) or extracortical (i. e. in the submeningeal
space) position. Pregnant mice subjected to X-
irradiation at a single dose of 1.5Gy on embryonic
day 13 which is the radiosensitive stage produced
offspring with neuronal heterotopia located in en-
larged lateral ventricles of the cerebral hemispheres
(Fig. 3) (49, 51, 53, 63). Midkine (MK) is a 13kDa
heparin-binding growth factor specified by aretinoic
acid-responsive gene. It is mitogenic for certain
fibroblastic cell lines, and enhances neurite out-
growth and survival of various embryonic neuron
types (121-123). Increased expression of MK was
detected on the processes of radial glial cells in the
developing rat cerebral cortex (124). Thus, MK is
used for analysis of gliogenesis in the early stages
of the developing brain. MK-immunocytochemical
staining (59-62) was carries out to confirm a course
corresponded to the distribution of the radial glial
fibers (neuronal pathway). These MK-staining fibers
radially traversed the distance between the ventricu-
lar zone and the pial surface. They were straight
and perpendicular to the pial surface, oriented in
the direction of neuronal migration in the normal
brain (Fig. 4A). However, in the brain of the irradi-
ated mice, MK-staining radial glial fibers (examination
from6hr after irradiation) were crumpled and no
longer regularly distributed to the pial surface
(Fig. 4B). It is well know that radial glial cells play
a role as guides for migrating neurons (50, 53),
while a large number of young neurons migrated
Fig. 3.
bellow the cerebral cortex (cc) of a1-week-old mouse irradiated
on embryonic day 13 (E 13), which corresponds to E 15in the
rat. Heterotopiais separated from the cerebral cortex by a band
offibers of corpus callosum (cf). cp: choroids, lv : lateral ventricle.
Hematoxylin and eosin stain. Scale bar=400 µm.
An example of a typical heterotopica (arrows) located
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along such adisturbed pathway, some of them could
not move far from the place of their origin around
the lateral cerebral ventricle and remained in the
lower inappropriate layer or near the ventricle to
formheterotopic cell mass (Fig. 5).
(2) Abnormal neuronal migration in mutant mice
Several studies on neurological mutant murine
with brain malformation (64, 65) provide a new
approach to the discovery of genetic loci that
contribute to neuronal migration in developing
brain. Classical studies of mutants, Reeler, Scrambler,
Yatari, have been assumed to be models for neuronal
migration in cerebral cortex. In Reeler mutant mice,
the cortical layering appears inverted (41). In other
words, the first cells of definitive cortex to migrate
out of the ventricular zone end up residing in the
superficial cortical plate and subsequent cells migrate
to and stop in progressively deeper positions. This
migration pattern is opposite of the normal inside
tooutside development of the cerebral cortex. The
affected gene in Reeler mice was found to encode
for a large extracellular matrix protein named Reelin
(29, 31, 66, 67). Reelin has homology to F-spondin
and contains epidermal growth factor-like repeats
similar to those of tenascin C, tenascin X, restrictin,
and the integrin βchain (31). Reelin is expressed
by Cajal-Retzius cells and is found extracellularly
in the molecular layer (layer I) (29, 31, 33). These
AB
Fig. 4.
radial glial fibers are straight and perpendicular to the pial surface in the control mouse. B : Radial glial fibers are crumpled and no
longer regularly distributed tothe pial surface in the mouse irradiated on embryonic day 13. Scale bar=100µm.
An example of anti-Midkine (MK)-immunoreactive radial glial fibers in the mouse brain mantle on embryonic day 17. A :
Fig. 5.
young neurons migrated along disturbed pathways in a1-week-
old mouse irradiated on embryonic day13. Some of these
neurons could not move far from the place of their origin
around the lateral cerebral ventricle and remained in the lower
inappropriate layer (arrows) or near the ventricle to form
heterotopic cell mass (arrowheads). Scale bar=100µm.
An example of anti-bromodeoxyuridine (BrdU)-labeled
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data suggest that Reelin is required for the normal
inside tooutside positioning of cells as they migrate
from the ventricular zone (25, 68). This was the first
component of a signaling pathway guiding cells to
the correct location in the cortex. Because Reelin
is an extracellular matrix molecule, a receptor for
Reelin would be required for signaling to the mi-
grating cells. Reelin signaling pathway was sum-
marized in Fig. 2. Reelin has been found to bind to
cadherin related receptor (CNRs) (69) and at least
two members of the LDL receptor family (70-72)
and α3β1-integrin (73). Binding of Reelin toα3β1-
integrin functions as a stop signal ; however, the
downstream components within the cell that regulate
the migration stop are not known. Upon contact
with Reelin, the CNRs initiates phosphorylation of
the cytoplasmic second messenger mDab1, possibly
through aCNR-associated tyrosine kinase Fyn (69)
or through the LDL receptor (71, 72). The scrambler
and Yotari mutant mice have been identified as
mutations in the mDab1gene (8). Scramber, Yotari,
and mDab 1-/-all show a Reeler phenotype further
supporting the notion that they lie the same path-
way. Phosphorylated mDab1can interact with a
variety of proteins including the SH2 domain of
Src (74). Src has been shown to interact with actin
and affect cytoskeletal remodeling (75-77). Src-
deficient cells exhibit strong adhesion to surfaces
and low migration capacity (78). Therefore, these
data tie Reelin signaling pathway to cell migration
and enable neurons to be targeted to the appropriate
layer of the cortex. mDab1 also activates the proto-
oncogene c-Ab1. Once activated, c-Ab1 can phos-
phorylate Cdk5, aprocess that is enhanced by Cable,
thus activating Cdk5 (79). Cdk5 and p35 (another
activator of Cdk5) have also been implicated in
directing neurons to the appropriate location within
the cerebral cortex (80-82). Cdk5 has several putative
kinase substrates and several other potential bio-
chemical interactions, in addition to an effect on
neurite outgrowth, all of which might have some
role in neuronal migration. Cdk5 can phosphorylate
both neurofilaments (115, 116) and the microtubule-
associated protein, tau (117, 118). Although the
mechanism by Cdk5 or p35 has its effects on
migration is not clear, all of the effects are related
to cytoskeletal changes. Cdk5 and p35 are highly
expressed in the developing central nervous system
and mice engineered to be homozygous mutant
for Cdk5or p35alsoshow acortical defect similar,
although not identical, to the Reeler phenotype
(80). Nikolic et al. have shown co-localization of
Cdk5, p53, Rac and Pak-1 in neurons (83). They
suggest that a Rac-dependent hyperphosphorylation
of Pak-1 results in a dynamic down-regulation of
actin polymerization and enhancement of new focal
complex formation during cell migration and process
outgrowth (83). Activation of Pak has also been
shown to result in a loss of stress fibers and focal
adhesions (84). These data indicate that the Rac
family of GTPases along with Scr family members
can regulate cytoskeletal remodeling and therefore
transduce guidance signals fromthe cell membrane
tothe cytoskeleton.
(3) Abnormal neuronal migration in the human brain
The genes mutated in several human disorders
of neuronal migration also provided a basis for
linking neuronal migration. In man, more than 25
syndromes with neuronal migration disorders have
been described (37). Neuronal migration disorders
primarily affect development of the cerebral cortex,
but the extent and nature ofthe cortical malformation
varies greatly (38). Table1summarized genetics of
neuronal migration, characteristics of the pathologic
alterations and underlying defect in some of these
syndromes both in mutant rodent models and
humans. It can provide important insights into the
histogenesis ofthe cerebral cortex and the molecular
etiology for the cerebral malformations.
Lissencephaly represents abroad class of neuronal
migration disorders. It can be described as a brain
with a macroscopically smooth cortical surface in
which amore or less layered cortex can be observed
on microscopical examination. It occurs as an isolated
abnormality (isolated lissencephaly sequence) or
in association with dysmorphic facial appearance
in patients with Miller-Dieker lissencephaly (85).
These abnormalities have been attributed todefects
in neuronal migration (86). A hemizygous chro-
mosomal deletion at band 17p13.3 led to identification
of lissencephaly-1 (LIS-1) as the causative gene in
this anomaly. The LIS-1 gene codes for the LIS1
protein, which contains eight WD-40repeats of the
type found in G-protein βsubunits. It is a regulatory
subunit of brain intracellular Platelet-Activating-Factor
acetyllhydrolase (PAF-AH1B1) (87), a G-protein-
like trimer that regulates cellular levels of the lipid
messenger PAF (88). The importance of PAFAH 1B 1
in the developing brain is supported by the high-
level expression of mRNA transcripts for all three
subunits during neuronal migratory epochs in
cerebrum. The LIS-1gene product is prominent in
Cajal-Retzius cells and ventricular neuroepithelium
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Table 1 Genes implicated in neuronal migration disorder
Mutation Symbol Chromosome Position Description
Source (No. of
references)
Mice
Reeler
Scrambler
Yotari
Disabled
Lissencephaly
Zellweger
Rats
Double cortex
Humans
MD syndrome
Lissencephaly
X-Linked
Lissencephaly
Zellweger
syndrome
Bilateral
Periventricular
Nodular band
Heterotopias
Microencephaly
rl
scr
yot
mdabI
Lis 1
PEX 1,
PEX 2
tish
LIS 1
LIS
xLIS
At least
10genes
proposed
BPNH
ND
5
4
4
4
ND
ND
ND
17
X
ND
X
1
8.0cM
49.7cM
49.7cM
49.7cM
ND
ND
ND
17p13.3
Xq 22.3-
q 23
ND
Xq 28
1q 25
Migration arrest in early development with subsequent
failure of cortical plate formation. Reeler encodes a
large ECM molecule produced by Cajal Retzius cells
in the molecular layer.
Phenotype is identical to that of reeler. Scrambler
is a mutation in a disabled gene that encodes a
phosphoprotein that binds nonreceptor tyrosine
kinases.
Allele of scrambler.
Allele of scrambler.
Failure offorebrainneuronal migrationviadeletionofth
ebetasubunit ofplatelet activatingfactor acetylhydrolase
(PAFAH1B1, alsoknown as Lis1)
Failure of forebrain neuronal migration viadefective
peroxisomal biogenesis.
Cortical neurons are seen in a bilateral heterotopia
that is prominent below the frontal and parietal
neocortex ; heterotopoas rare beneath the temporal
cortex.
A class of spontaneous and inherited disorders (MD)
with failure of migration in forebrain, fewer gyri, and
smoother gyri in cerebral cortex. In amurine model,
the mechanism involves the deletion of the beta-subunit
of platelet activating factor acetyldehydrogenase
(PAFAH1B1).
Subset of MD with failure of migration in forebrain.
Individuals that express the gene have a smooth
brain, i.e. fewer gyri in the cerebral cortex.
Males show lissencephalic phenotype. Females have
adouble cortex phenotype with disorganized forebrain
gray matter and an extra layer of cells located
underneath the white matter.
The defective gene encodes the doublecortin protein.
Doublecortin is homologous to the amino terminus
of apredicted protein kinase, which suggests a role
for signal transduction.
Failure of cortical migration, neuronal laminae do
not form. In two murine models, the molecular
mechanism involves defects in the PEX 2 or PEX 5
genes, both genes required for neuronal peroxisomal
biogenesis.
Forebrain neurons form heterotopias in the
subependymal zone. The cellular mechanism is
unknown.
A class ofdisorders resulting inreduced brainsize due
tosmaller neuronal lamina. The pattern of lamination
isnormal ; the thickness of the layers is reduced.
(Nor involving head structures.) One subgroup of
families has been mapped.
29, 103, 104.
105, 106.
8, 107.
8.
104.
101, 102.
111.
112.
113.
92, 93, 94.
112.
96, 97, 114.
ECM : extracellular matrix, EGF : epithelial growth factor, ND : not determined, MD : miller-Dieker.
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in developing human cortex (89). How the absence
of the LIS-1 gene product affects PAF-AH1B1
function, PAF signaling in the cell, and ultimately
neuronal migration remains to be understood. In
addition, LIS-1 may have ad yet unidentified inter-
actions in the cell, as suggested by the ability of the
WD-40 repeat segments of LIS-1 to interact with
the cytoskeketon. The normal geneproductofLIS1
is widely distributed in the grey and white matter of
the brain and spinal cord in controls. It has been
found both in neurons and in glial cells (90). Prenatal
diagnosis ofthe chromosome band 17p13.3deletionis
now possible using Fluorescent In Situ Hybridization
(FISH) and Fragment Restriction Length Polymor-
phism (FRLP) techniques after chorionic villus
biopsy sampling. Another group of disorders with
this general class of neuronal migration disorder
is X-linked (86). The first X-linked malformation
syndrome is X-linked LIS. In X-LIS, hemizygous males
have lissencephaly and heterozygous females have
subcortical band heterotopia that is also known as
adouble cortex (DC) syndrome. The clinical presen-
tation in affected males is similar tothat with classical
lissencephaly and chromosome 17p 13.3 deletion :
profound mental retardation, epilepsy with multiple
seizure types, feeding problem and a shortened life
span. The female carriers have mental retardation,
behavior problems and epilepsy. Linkage of DC/X-
LIS to Xq21-24 was first demonstrated (92, 93).
Subsequent positional cloning identified a novel gene
named Doublecortin (93, 94). Doublecortin is a
microtubule-associated protein which is expressed
widely by migrating neurons (11). It is often possible
topredict this gene mutation fromcareful review of
brain imaging studies : mutations of frontal gradient
of lissencephaly, whereas mutations of X-LIS are
associated with a frontal to occipital gradient (95).
The second X-linked malformation syndrome is
bilateral periventricular nodular heterotopia (BPNH)
that consists of BPNH in females and prenatal
lethality or amore severe phenotype in males. In this
disorder, large neuronal masses of well-differentiated
cortical neurons fill the adult subependymal zone.
The syndrome is located at Xq 28 (96-98) the cor-
responding gene was identified as Filamin 1 (FLN 1),
which encodes an actin-cross-linking phosphoprotein
which is required for movements of many cell
types (104).
Zellweger syndrome is a second broad class of
cortical malformation, causing death within approxi-
mately six months of life (91). Like lissencephaly,
Zellweger patients have characteristic gryal abnormali-
ties in the cerebral cortex, which show a stereotypic
medial pachygyria(reduced number of gyri, but they
are abnormally large) and lateral polymicrogyria
(excess number of small gyri). This syndrome is a
genetically heterogeneous disorder that may arise
from defects on at least 10 different genes (100).
Recently, animal models for a human of Zellweger
syndrome have provided by targeted deletion in mice
of genes encoding the PEX2 peroxisomal membrane
protein (101) and the PEX5peroxisomal protein
import receptor (102, 119). The PEX5-knockout
mouse models for Zellweger syndrome show that
deficient peroxisomal β-oxidation does not cause
neuronal migration defects by itself, but there are
some hints that the inactivity of some metabolic
pathway may contribute to the brain pathology in
mice and patients with complete absence of functional
peroxisomes (108, 120).
CONCLUSION REMARKS
Neuronal migration is the critical cellular process
which initiates histogenesis of cerebral cortex.
Migration involves aseries of complex cell interac-
tions and transformation. Postmitotic cells must first
adopt acharacteristic conformation prior to movement.
The cells are then guided in their ascent by contact
with the surface of aspecialized of the astroglial
lineage, the radial glial cells. When migrating cells
enter the cortical plate, neuronal cells migrate through
the established neuronal lamina and settle onto the
outermost layer, forming an “inside-out” gradient of
maturation. The process of neuronal cell migration
is highly sensitive to various physical, chemical
and biological agents as well as to genetic mutations.
Disturbance of neuronal migrating pathway (radial
glial fiber) or extracellular factors or correct settling
of Cajal-Retzius cells is considered for all types of
neuronal migration. Arrested or excessive migration
will lead neurons to differentiate in a hetertopic
position. Such neuronal migration disorder is believed
as major cause of both gross brain malformation
and more special cerebral structural and functional
abnormalities in experimental animals and humans.
An increasing number of instructive studies on
nongenetic models (e.g. MAM-or irradiation-treated
rodents) and mutations (e.g. reelin-or tish-mutant
animals) have established the foundation of cortex
formation and provided a framework in which to
understand the cerebral cortex development. These
experimental analysis and genetic manipulation
X. Z. Sun et al. migration of cortical neurons
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have come to together to begin providing detailed
explanation for the pathogenesis of several the
human phenotypes resulting from abnormal neuronal
migration. Linking the known genes into pathways
from extracellular signaling to cytoskeletal dynamics
will be important for a complete understanding of
the processes involved. Finding additional molecules
in these pathways along with defining the genetic
defects in other families and other syndromes will
also provide deeper insights into the genetic and
molecular mechanisms underlying normal and
abnormal neuronal migration.
ACKNOWLEDGEMENTS
The authors would like to thank Ms. Kiyoko
Suzuki and Ms. Yasuko Koto of Environmental and
Toxicological Sciences Research Group, National
Institute of Radiological Sciences for kind help in
retrieval of scientific references for this review.
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