Mechanisms and Disturbances of Neuronal Migration the Developing Nervous System: a Series of Review Articles

The Developing Nervous System: A Series of Review Articles

The following article is the ﬁrst in an important series of review articles which discuss the developmental biology of the nervous system and its relation to diseases and disorders that are found in new born infants and children. This review, by Pierre Gressens, describes neuronal migration in the developing brain and abnormalities in humans resulting from aberrations in neuronal migration.

Alvin Zipursky Editor-in-Chief

Mechanisms and Disturbances of Neuronal Migration

PIERRE GRESSENS

Service de Neurologie Pédiatrique and INSERM E 9935, Hôpital Robert-Debré, F-75019 Paris, France

ABSTRACT

Neuronal migration appears as a complex ontogenic step of migration of neurons destined to the neocortex. New insights occurring early during embryonic and fetal development. Control gained from the analysis of animal models as well as from the of neuronal migration involves different cell populations includ- study of human diseases will be included. (Pediatr Res 48: ing Cajal-Retzius neurons, subplate neurons, neuronal precursors 725–730, 2000) or radial glia. The integrity of multiple molecular mechanisms, such as cell cycle control, cell-cell adhesion, interaction with extracellular matrix protein, neurotransmitter release, growth Abbreviations: factor availability, platelet-activating factor degradation or trans- BDNF, brain-derived neurotrophic factor duction pathways seems to be critical for normal neuronal mi- EGF, epidermal growth factor gration. The complexity and the multiplicity of these mecha- NMDA, N-methyl-D-aspartate nisms probably explain the clinical, radiologic and genetic NT, neurotrophin heterogeneity of human disorders of neuronal migration. The PAF, platelet-activating factor present review will be focused on mechanisms and disturbances Tish, telencephalic internal structural heterotopia

During neocorticogenesis, neurons derive from the primitive form a subpial preplate or primitive plexiform zone (Fig. 1A). neuroepithelium and migrate to their appropriate position in the Subsequently produced neurons, which will form the cortical cerebral mantle. In humans, migration of neocortical neurons plate, migrate into the preplate and split it into the superficial occurs mostly between the 12th and the 24th weeks of gesta- molecular layer [or layer I or marginal zone containing Cajal- tion (1). In laboratory rodents, including mice, rats and ham- Retzius neurons (5)] and the deep subplate (Fig. 1A). Schemat- sters, this ontogenic step roughly extends from embryonic day ically, the successive waves of migratory neurons will pass the twelve to the first postnatal days, although interspecies differ- subplate neurons and end their migratory pathway below layer ences do exist (2–4). The first postmitotic neurons produced in I, forming successively (but with substantial overlap) cortical the periventricular germinative neuroepithelium will migrate to layers VI, V, IV, II, and II (inside-out pattern) (Fig. 1). The analysis of neuronal migration disorders occurring in humans and animal models has expanded our knowledge of Received May 26, 2000; accepted June 29, 2000 Correspondence and reprint requests: Pierre Gressens, Service de Neurologie Pédi- migratory mechanisms (6, 7). Because of a failure of normal atrique and INSERM E 9935, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 migration, neurons may accumulate in unusual areas (hetero- Paris, France. This work was supported by the INSERM, the European Community (Biomed grant) topias). Neuronal heterotopias can be focal (nodular heteroto- and the Fondation Grace de Monaco. pias) and located at all levels of the migration pathway, from

725 726 GRESSENS the lateral ventricle up to the cortical plate itself. Sometimes, The phenotype of radial glia seems to be determined both by over migration is observed with neurons present in the molec- migrating neurons and by intrinsic factors expressed by glial ular layer or even in the meninges. On the other hand, migra- cells. Among the latter, Götz et al. (14) recently demonstrated tory disorders can appear as diffuse band heterotopias in the that the transcription factor Pax6, which is specifically local- white matter (pachygyrias/lissencephalies, double cortex ized in radial glia during cortical development, is critical for syndrome). the morphology, number, function and cell cycle of radial glia. Radial glia and migratory pathways. During neocorticogen- From the appearance of the cortical plate, the radial glial fibers esis, migrating neurons can adopt different types of trajectories are grouped in fascicles of five to eight fibers in the interme- (Fig. 1B): 1) a large proportion of neurons migrate radially, diate zone (15, 16). The final cortical location of the neurons, along radial glial guides, from the germinative zone to the which could be determined by the guiding glial fascicle (see cortical plate (8). Radial glia are specialized glial cells present above), partly determines the connections the neuron will be in the neocortex during neuronal migration; these cells display able to establish. The fascicles of glial fibers, filled with a radial shape with a nucleus located in the germinative zone, glycogen could also provide energy supply for migrating neu- a basal process attached on the ventricular surface and a radial rons which are far away from developing blood vessels. apical process reaching the pial surface. Rakic (9) has postu- The ontogenic unit made of the radial glial fascicle is very lated that these radially arranged glial guides keep a topograph- similar in the mouse, rat, hamster, cat, and in the human (16). ical correspondence between a hypothesized protomap present Because this glial unit is constant throughout the mammalian in the germinative zone and the cortical areas. 2) An important species studied, it could represent the basic developmental group of neuronal precursors initially adopt a tangential trajec- module of the developing cortex: the unit remains stable while tory at the level of the periventricular germinative zone (10) the number of adjacent units gradually increases to permit before adopting a classical radial migrating pathway along brain expansion in the evolution of mammalian species. radial glia. This tangential migration could permit some dis- Knowledge of the genetic and environmental factors that con- persion at the level of the cortical plate of neurons originating trol the organization, number and function of these glial fas- from a single clone in the germinative neuroepithelium, in- cicles could, therefore, improve our understanding of cortical creasing the clonal heterogeneity within a given cortical area. development and evolution of the brain (17, 18). 3) Tangentially migrating neurons have also been described at Effects of neurotransmitters and growth factors on neuro- the level of the intermediate zone (prospective white matter) nal migration. Komuro and Rakic (19) first reported that (11). Recent studies (12, 13) suggest that most of these neu- specific inhibitors of the N-methyl-D-aspartate (NMDA) glu- ronal cells displaying a migrating pathway orthogonal to radial tamate receptor subtype slowed down the rate of in vitro glia originate in the ganglionic eminence. GABA-expressing neuronal migration. Further demonstration that glutamate plays interneurons seem to be produced by this mechanism. a role in neuronal migration was given by Marret et al. (20).

Figure 1. (A) Schematic illustration of mammalian neocortical formation. GZ, germinative zone; IZ, intermediate zone (prospective white matter); PPZ, primitive plexiform zone; SP, subplate; I, cortical layer I or molecular layer; II to VI, cortical layers II to VI. Arrows and light gray circles indicate migrating neurons while black circles and triangles represent postmigratory neurons. (B) Coronal neopallial section at 15 wk of gestation showing a schematic representation of the different migratory pathways adopted by neurons. 1: radial migration along radial glial cells of neurons originating from the periventricular germinative zone (GZ). 2: Tangential migration in the germinative zone (GZ) followed by a radial migration along glial guides. 3: Tangential migration in the intermediate zone (IZ) of neurons originating from the ganglionic eminence. M, meninges; I, layer I or molecular layer; V-VI, cortical layers V and VI; LV, lateral ventricule. NEURONAL MIGRATION 727 They performed focal injections of ibotenate, a glutamate slow polymerization combined with fast disintegration of ori- analog mainly acting on NMDA receptors, into the brain of ented microtubules was critical for displacement of the nucleus hamsters on the day of birth, a stage where neurons destined to and cytoplasm within the membrane cylinder of the leading the superficial cortical layers are migrating. The resulting process of the migrating neuron. pattern was a laminar band heterotopia (see below), focal Type I lissencephaly and platelet-activating factor (PAF). periventricular nodular heterotopias or intracortical arrests of Lissencephaly and agyria-pachygyria are the terms used to migrating neurons. Ibotenate, a unique molecular trigger of the describe brains with absent or poor sulcation. Agyria refers to excitotoxic cascade, produces a wide spectrum of abnormal brains or portions of brains with absence of gyri and sulci neuronal migration patterns encountered in the human brain whereas pachygyria refers to brains or portions thereof with such as nodular heterotopias, lissencephalies and double cortex few broad, flat gyri and shallow sulci. Lissencephaly (“smooth syndromes. brain”) is another term used to describe such brains. Complete GABA is also involved in neuronal migration modulation as lissencephaly is synonymous with agyria, whereas incomplete it stimulates, in tissue culture, neuronal migration via calcium- lissencephaly refers to brains with shallow sulci and a rela- dependent mechanisms (21). Growth factors have been re- tively smooth surface; incomplete lissencephaly is often use cently implicated in the control of neuronal migration. Intra- synonymously with agyria-pachygyria. ventricular injection of neurotrophin-4 (NT-4) (22) or over Type I lissencephaly (Fig. 2B) usually has both agyric and expression of brain-derived neurotrophic factor (BDNF) (23) pachygyric regions (26). The histologic appearance of the produce heterotopic accumulation of neurons in the molecular cortex varies according to the brain area; the majority of the layer (layer I), mimicking some aspects observed in human neocortex is that of a “4-layered” cortex, composed of a status verrucosus deformans. molecular layer, a disorganized outer cellular layer, a cell X-linked periventricular heterotopia. The human X-linked sparse layer, and an inner cellular layer (probably composed of dominant periventricular heterotopia (Fig. 2A) is characterized neurons whose migration has been prematurely arrested). The by neuronal nodules lining the ventricular surface. Hemizy- migratory defect is postulated to occur between 12 and 16 gous males die during the embryonic period and affected gestational weeks. Miller-Dieker syndrome is a malformative females have epilepsy which can be accompanied by other syndrome associating classical type I lissencephaly and a manifestations such as patent ductus arteriosus and coagulopa- characteristic facies. thy. The gene responsible for this disease has been recently Clinically, the head size is normal to small at birth but identified (24): filamin 1 (FLN1) encodes an actin-cross- progressive microcephaly over the first few years of life is linking phosphoprotein which transduces ligand-receptor bind- common. Patients are hypotonic at birth and develop progres- ing into actin reorganization. Filamin 1 is necessary for loco- sive spasticity. Seizures usually begin within the first few motion of several cell types and is present at high levels in the months of life. developing neocortex. Rakic et aI. (25) had previously shown Miller-Dieker syndrome and up to 40% of cases of isolated the polarity of microtubule assemblies during migration of lissencephaly sequence (27) result from a hemideletion or rodent cerebellar neurons and proposed that the dynamics of mutations of the LIS1 gene. LIS1 encodes the beta subunit of

Figure 2. (A) X-linked periventricular heterotopias. Arrows indicate nodules of heterotopic neurons which failed to migrate to the cortical plate and remained blocked in the periventricular zone. (B) Type 1 lissencephaly. CT-scan showing the typical 8-shape picture. Note the smooth (agyric) surface of the brain, the presence of heterotopic neurons (arrows) in the white matter and the enlarged lateral ventricles. (C) Double cortex syndrome. Arrows point to the normally localized cortical plate while stars indicate the laminar band heterotopia. (A and C: courtesy of Dr. Thierry Duprez, Service de Radiologie, St-Luc Hospital, University of Louvain Medical School at Brussels, Belgium). 728 GRESSENS a brain acetylhydrolase which degrades platelet-activating fac- internal structural heterotopia) rat. The tish rat is a spontane- tor (PAF). Accordingly, in vitro stimulation of PAF receptor ously mutant animal exhibiting a bilateral laminar band hete- disrupts neuronal migration (28) and mice with one inactive rotopia which predominates in the frontal and parietal cortex LIS1 allele display cortical and hippocampal neuronal migra- (38). The heterotopic cortical plate could be secondary to the tion delay (29). PAF is an ether phospholipid acting in the combination of abnormal neuronal migration and heterotopic brain on receptors present on synaptic endings and intracellular neurogenesis. Affected rats exhibit spontaneous recurrent elec- membranes. As PAF increases intracellular calcium concentra- trographic and behavioral seizures. tion and increases NMDA receptor currents, it is tempting to Zellweger syndrome. The Zellweger cerebro-hepato-renal speculate that some of brain abnormalities observed in Miller- syndrome is a fatal autosomic recessive disease caused by an Dieker syndrome are secondary to an excess of glutamatergic absence of functional peroxisomes. One hallmark of this hu- transmission, potentially linking the above described hamster man disease is the presence of heterotopic neurons in the model of migration disorder to human lissencephaly. An alter- neocortex, the cerebellum and the inferior olivary complex. native hypothesis is that PAF acetylhydrolase could be a link to Patients are characterized by the absence of psychomotor the microtubule network and motility apparatus in migrating development or a rapid regression, a dysmorphic facies and a neurons (7). severe hypotonia; they generally die within a few months. Studying human fetuses, Clarck et al. (30) have shown that Animal models of this human disease have been produced by LIS gene products are localized in Cajal-Retzius neurons, some inactivation of a gene critically involved in peroxisomal as- subplate neurons, thalamic neurons and in the periventricular sembly (39, 40). Homozygous animals for the gene inactiva- germinative zone. The expression of LIS in Cajal-Retzius cells tion have no functional peroxisomes, die around birth and strongly support the previously suspected role of these cells in display heterotopic neurons in the subcortical white matter and the neuronal migration and in the cytoarchitectonic organiza- dysplastic olivary complex. The study of radial glia cells did tion of the cortical plate. Previous studies have suggested that not reveal any significant morphologic change although the subplate neurons could interact with migrating neurons (31), available data do not permit one to exclude a functional defect. although the precise effects of these subplate neurons on Analysis of mutant mice revealed that the migration defect was neuronal migration have not yet been reported. Finally, the caused by altered N-methyl-D-aspartate (NMDA) glutamate presence of LIS gene product in the germinative zone is in receptor-mediated calcium mobilization (41). This NMDA re- agreement with other studies which have shown that laminar ceptor dysfunction was linked to a deficit in PAF, a phenom- distribution of cortical neurons is influenced by events occur- enon related to peroxisome impairment. These findings con- ring during the mitotic cycle of neuronal precursors in the firm NMDA receptor and PAF involvement in neuronal germinative zone (32). migration and suggest a link between peroxisome metabolism Double cortex syndrome. Diffuse subcortical laminar hete- and NMDA receptor efficacy. rotopias (Fig. 2C) have been described pathologically as well Effects of environmental factors on neuronal migration. as on clinical and imaging basis under the names of “double Neuronal migration disorders have been described in hu- cortex,” “bicortical lissencephalies,” “partial lissencephalies,” mans and/or in animal models following in utero exposure or “laminar band heterotopias” (26). In this brain malforma- to several environmental factors, including infection with tion, two cortical plates, separated by white matter, co-exist: cytomegalovirus (42) or toxoplasmosis (Evrard and Gadis- one cortical plate is in a normal superficial position while the seux, unpublished observation), ethanol (3, 43, 44), cocaine other one is located in a deep heterotopic position and is (45, 46) or ionizing radiation (47). In most cases, the separated from the lateral ventricle by another area of white mechanisms by which these factors disturb neuronal migra- matter. It seems that different clinical conditions have been tion remain unclear. Prenatal cocaine administration to described under these names: reported patients have usually pregnant mice or monkeys induces abnormal addressing of moderate to severe developmental delay and an early onset of neurons in the neocortical plate (45, 46). This abnormal medically refractory seizures but other patients can have rela- neuronal migration pattern is probably linked to the ob- tively mild clinical manifestations. Des Portes et al. (33) and served abnormalities of radial glia density and disturbances Gleeson et al. (34) have recently identified a novel gene (DCX of neuronal proliferation in the germinative zone. or XLIS gene) involved in X-linked neuronal migration disorder where females display subcortical laminar heterotopia (or double cortex syndrome) while lissencephaly is found in CONCLUSION males. The gene encodes a protein, doublecortin, which is a microtubule-associated protein expressed by migrating and A few human and rodent genes and factors linked to differentiating neurons (35, 36), again emphasizing the impor- neuronal migration disorders have been recently identified tance of the cytoskeleton for neuronal migration (7, 25). From (Table 1). The elucidation of their function should help to a clinical point of view, a recent report has proposed that clarify the mechanisms of neuronal migration as well as the deletions or mutations of DCX and LIS1 genes account for pathophysiology of some brain malformations. Furthermore, 76% of isolated type I lissencephalies (37). these diseases can now benefit from a genetic diagnosis Two animal models of laminar band heterotopias are cur- which can also be applied in some instances to prenatal rently available: the ibotenate-induced laminar heterotopias in cases. Improvement of imaging techniques has provided the newborn hamster (see above) and the tish (telencephalic new classifications of neuronal migration disorders as well NEURONAL MIGRATION 729

Table 1. Summary of the established or hypothetical links between genes and gene products and neuronal migration disorders in human and rodent neocortex (adapted and modiﬁed from Gressens, 1998) LIS1 gene, PAF Miller-Dieker syndrome and some isolated type I lissencephalies DCX or XLIS gene X-linked subcortical laminar heterotopia and lissencephaly syndrome (or double cortex syndrome) Filamin 1 (FLN1) X-linked dominant periventricular heterotopia Tish gene Laminar band heterotopias, double cortex syndrome Reelin Inverted cortical layers p35/cdk5 kinase Inverted cortical layers Neurotrophins Status verrucosus, molecular ectopias, inverted cortical layers GABAergic system Neuronal migration disorders Glutamatergic system Neuronal heterotopias, molecular ectopias Peroxysomal apparatus Zellweger syndrome Pax6 gene Abnormalities of radial glia

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