Normal and abnormal
neuronal migration in the developing cerebral cortex
Xue-Zhi Sun, Sentaro Takahashi,
Chun Cui*, Rui Zhang, Hiromi Sakata-Haga*, Kazuhiko Sawada*
and Yoshihiro Fukui*
|
Environmental and Toxicological Sciences Research
Group, National Institute of Radiological Sciences, Chiba,
Japan;and *Department of Anatomy and Developmental Neurobiology,
The University of Tokushima School of Medicine, Tokushima,
Japan
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
INTRODUCTION
The development of the mammalian cerebral cortex is a remarkably
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 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 understanding 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 relationship to cerebral
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 a precocious 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 of the ventricular zone and settle between these two layers
to engage into a long migration with radial centrifugal fashion
through the intermediated 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 progressively 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 top of the cortical plate facing
the marginal layer cells.
Neuronal migration in the neocotex takes place for the greater
part between the 8th and 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 to the astroglial
cell lineage. During cortical development, these long bipolar
cells expand radially across the thickness of the cerebral
wall. Radial glia are bipolar cells with one short process
extended to the adjacent ventricular surface and a second
projecting to the 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 successive 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
completed, when the morphology of radial glial cells changes
into that 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 determining
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 to be provided by the most superficial cortical layer
or the pial membrane. This process of the neuronal migration
stop involves the detachment from the 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 of mouse mutants has led to identify
some of the molecules that regulate neuronal positioning.
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 form a Reelin's zone to stop migration
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 to end 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 a profound and stereotypical malformation. Various environmental
factors (teratogenic, physical and biological factors) which
can affect neuronal migration 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 migration 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 to differentiate 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 of1.5Gy on embryonic day
13 which is the radiosensitive stage produced offspring with
neuronal heterotopia located in enlarged lateral ventricles
of the cerebral hemispheres (Fig. 3) (49, 51, 53, 63). Midkine
(MK) is a 13kDa heparin-binding growth factor specified by
a retinoic acid-responsive gene. It is mitogenic for certain
fibroblastic cell lines, and enhances neurite outgrowth 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 ventricular
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 irradiated 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
along such a disturbed 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 form heterotopic 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 to outside 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 data suggest that Reelin is
required for the normal inside to outside 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 migrating cells. Reelin signaling pathway
was summarized 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 to α3β1-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
a CNR-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 mDab1-/-all show a Reeler phenotype further supporting
the notion that they lie the same pathway. 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 phosphorylate
Cdk5, a process 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 biochemical
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 Cdk5 or p35
also show a cortical 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 from the
cell membrane to the 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 25syndromes with neuronal migration disorders have
been described (37). Neuronal migration disorders primarily
affect development of the cerebral cortex, but the extent
and nature of the cortical malformation varies greatly (38).
Table1 summarized 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 of
the cerebral cortex and the molecular etiology for the cerebral
malformations.
Lissencephaly represents a broad class of neuronal migration
disorders. It can be described as a brain with a macroscopically
smooth cortical surface in which a more 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 to defects in neuronal migration (86).
A hemizygous chromosomal 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-40 repeats 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 PAFAH1B1 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 in developing human
cortex (89). How the absence of the LIS-1 gene product affects
PAF-AH1B1function, PAF signaling in the cell, and ultimately
neuronal migration remains to be understood. In addition,
LIS-1 may have ad yet unidentified interactions in the cell,
as suggested by the ability of the WD-40 repeat segments of
LIS-1 to interact with the cytoskeketon. The normal gene product
of LIS1 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
of the chromosome band 17p 13.3 deletion is now possible using
Fluorescent In Situ Hybridization (FISH) and Fragment Restriction
Length Polymorphism (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 a
double cortex (DC) syndrome. The clinical presentation in
affected males is similar to that with classical lissencephaly
and chromosome17p 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 to predict
this gene mutation from careful 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 a more 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 Xq28 (96-98) the corresponding gene was identified
as Filamin 1 (FLN1), 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 approximately six months of life (91).
Like lissencephaly, Zellweger patients have characteristic
gryal abnormalities 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 PEX5 peroxisomal
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
a series of complex cell interactions and transformation.
Postmitotic cells must first adopt a characteristic conformation
prior to movement. The cells are then guided in their ascent
by contact with the surface of a specialized 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 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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Received for publication May 31, 2002;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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