New directions for neuronal migration

45

New directions for neuronal migration Alan L Pearlman*, Phyllis L Faustt, Mary E Hatten and Janice E Brunstrom§ Analysis of genetic mutations that lead to abnormal migration and layer formation in the developing cerebral cortex of mice and humans has led to important new discoveries regarding the molecular mechanisms that underlie these processes. Genetic manipulation and experimental analysis have demonstrated significant tangential migrations of cortical neurons, some arriving from very distant noncortical sites.

Addresses *§Departments of Neurology and Cell Biology, Washington University School of Medicine, 660 South Euclid, St Louis, Missouri 63110, USA *e-mail: [email protected] §e-mail: [email protected] tDepartment of Pathology, Columbia University, 630 West 168th Street, New York, New York 10032, USA; e-mail: [email protected] SLaboratoryof Developmental Neurobiology, The Rockefeller University, 1230 York Avenue, New York, New York 10021-6399, USA

Current Opinionin Neurobiology 1998, 8:45-54 http://biomednet.com/elecref/0959438800800045 © Current Biology Ltd ISSN 0959-4388

Abbreviations ASTN BPNH CSPG ECM EGF

GABA ILS IZ kb LGE LIS MZ NMD NT4 PAF PAF-AH SBH SGL SMZ VZ

astrotactin bilateral periventricular nodular heterotopia chondroitin sulfate proteoglycan

extracellularmatrix epidermal growth factor ~,-aminobutyricacid isolated lissencephaly sequence intermediate zone kilobases lateral ganglionic eminence lissencephaly marginal zone neuronal migration disorder neurotrophin-4 platelet-activating factor PAF acetylhydrolase subcortical band heterotopia subpial granule cell layer subventricular zone ventricular zone

Introduction T h e neuronal migrations that establish the cerebral and cerebellar cortices are among the most dramatic of the developmental steps that form the nervous system. Neurons travel along pathways that are long and crowded, then form discrete layers that are anatomically and functionally distinct. T h e general questions that dominate the study of neuronal migration are compelling: how do neurons recognize and attach to their migratory substrate, how do they generate the forces that move them forward,

and how do they recognize the journey's end and form laminar assemblies? T h e long processes of radial gila support and guide the migration of a large proportion of the neurons that form cortical structures. Glial-guided migration has been the subject of several recent reviews [1M], and thus will be covered only briefly here. We will concentrate on two relatively new directions for the field: first, mutations in rodents and humans that affect migration and layer formation and that are providing surprising new avenues for exploration; and second, a recently defined set of long, tangential migrations that are not guided by radial gila.

Astrotactin provides a n e u r o n a l ligand for migration A number of neuronal and g]ial receptor systems have been implicated in the directed migration of CNS neurons along astroglial substrates ([5-7]; for reviews of earlier reports, see [3,4]). Neuregulins, which are secreted growth factors, are produced by neurons in both the developing cerebellum and cerebral cortex, whereas their receptors (erbB2, crbB3 and erbB4) are expressed by both neurons and glia [8",9"']. Experimental evidence indicates that neuregulins affect neuronal migration as well as the growth and differentiation of radial gila [8°°,9"]. T h e neuronal protein astrotactin (ASTN) has been the most extensively studied receptor system in functional assays of glial-guided neuronal migration. Antibody perturbation assays demonstrate that A S T N provides a ligand for neuronal binding to the glial fiber during migration. Although other surface receptor systems can support neuronal movement, removal of A S T N reduces the rate of neuronal locomotion by approximately 60%. Molecular cloning of astn indicates that its predicted protein product has a unique structure among neuronal adhesion molecules. Although A S T N has regions of homology with adhesion molecules of the fibronectin III and epidermal growth factor (EGF) families, it is not a member of the immunoglobulin gene superfamily. ASTN mRNA is expressed in postmitotic neurons undergoing migration away from germinal zones in cerebellum, hippocampus and cortex [10"]. Thus, A S T N functions in a receptor system that controls the rate of neuronal migration along glial fibers, enabling the rapid movement of large populations of young neurons to form cortical laminar assemblies.

N e u r o n a l migration in n e u r o l o g i c a l m u t a n t mice Studies on neurological mutant mice with brain malformations have provided another approach to the discovery

46

Development

of genetic loci that contribute to neuronal migration in developing brain. Two of these mutants, aa,eaver and reelel; have long been assumed to be models for cell migration. In wea~'er mice, granule cell precursors in the cerebellar cortex fail to migrate along glial fibers and die in ectopic positions. In vitro studies [11] and the production of mouse chimeras [12] have demonstrated that the aveaver gene acts in the immature neuron. Positional cloning of ~'ecr~,er [131 confirmed the cellular site of action of the gene, but, surprisingly, the developmental defect results from a gain-of-function point mutation in the G-protein-gated inwardly rectifying potassium (GIRK2) channel [14-16[. T h e latter leads to death of the neuron, prior to migration. Even though studies on aa,eaver point to a role for channels hitherto silent during development, they have not yielded insights into genetic pathways that control neuronal migration.

l'he reeler mutant mouse T h e reeler mutation, first described over 45 years ago, produces abnormal architecture in many parts of the brain, but the disruption is most dramatic in the cerebral and cerebellar cortices [17,18].

In the normal deve]opment of the cerebral cortex, the earliest postmitotic neurons form the preplate (also called the primordial plexiform zone), just above the zone of active proliferation adjacent to the cerebral ventricle (also called the ventricular zone, or VZ). T h e preplate consists of at least two populations from the outset: upper and lower preplate cells. Cells in the upper preplate are generated slightly earlier, and many express reelin (see below) and calretinin. T h e two populations are divided by arriving cortical plate neurons: the upper population becomes the marginal zone above thc cortical plate and the lower preplate cells form the subplate, below the cortical plate (Figure 1). T h e earliest cortical plate neurons become the deepest cortical layer; subsequent waves of neurons migrate past their predecessors to form cortical layers in a well-defined 'inside-out' fashion. In reeler cortex, although cell generation and the initial phases of migration are normal, the preplate is not split into two layers by the cortical plate cells [19,20]. Cajal-Retzius neurons, identified by their expression of calretinin, remain at the top of the undivided preplate [21] or 'superplate'. Cortical plate neurons accumulate beneath the superplate in a highly disordered, nonlaminar fashion [17,18,22,23] (Figure 1). T h e reeler gene (recently renamed tee/in; abbreviated as re/n), identified by insertional mutagenesis [24] and positional cloning [25,26], codes for a very large extracellular matrix (ECM)-like protein, reelin. Ree/in contains 65 exons spread over 450 kb of genomic D N A [27]. T h e predicted amino acid sequence [24] and expression studies [28"] demonstrate that reelin is secreted. It has homology

to F-spondin, and contains EGF-like repeats that are similar to those of tenascin C, tenascin X, restrictin, and the integrin beta chain [24]. T a k e n together, these observations have led to the suggestion that reelin is an ECM-like protein that may interact with other adhesive proteins and mediate cell adhesion [24]. All of the mutant alleles of :'eelin have the same cortical phenotype, and all lack secreted reelin [24,29,30]. A mutant rat with an identica] phenotype has also been described [31]. T h e human tee/in gene, located on chromosome 7q22, is nearly identical to that of the mouse, but thus far no links have been established to human pathology [32]. T h e distribution of reelin is particularly intriguing with regard to its possible functional role in cortical devclopment. Reelin is produced by tile Cajal-Retzius neurons in the outer aspect of the preplate that comprise a subset of cells in the marginal zone after cortical plate formation I21,24,28°,33,341 (Figure 1). In contrast, fibronectin and chondroitin sulfate proteoglycans (CSPGs), including neurocan, are prominent throughout the preplate [35,361. As the cortical plate forms, fibronectin, CSPGs, and hyaluronectin remain in close association with tim former preplate cells in their new locations, the marginal zone and subplate, and are very sparse in the cortical plate itself [35,361 (Figure 1). T h e close association of ECM components and preplate cells is maintained in reeler cortex, even though preplate cells remain in a single layer, undivided by cortical plate formation [201 (Figure 1). Reelin is thus the only ECM component identified to date that is produced by cells in the upper preplate and in the marginal zone, but not by cells in the subplate. Reelin is neither produced by nor distributed along radial glia, supporting many earlier observations that only the termination of migration and layer formation are abnormal in reeler mice [17,18]. However, reelin in the upper preplate and the marginal zone is suitably positioned to provide a stop signal to cells at the end of their journey [20,37]. Without reelin in the marginal zone, cortical neurons might reverse direction as they do in cell culture, then migrate downward and accumulate beneath the preplate, often in inverted orientation. Failure to contact reelin might also result in failurc to express the surface molecules necessary for aggregating as discrcte layers [21,38"°1. Alternatively, reelin might serve as a scaffold for the attachment of peptide growth factors that would provide these differentiation signals. Several other hypotheses involving abnormalities in net, ton-gila or neuron-neuron interactions have been put forward to explain the :ee/e:" defect [39,40], including the prospect that reelin in the marginal zone repels subplate neurons, allowing a space for the formation of the cortical plate [21,41°1, or repels invading cortical plate neurons, preventing their entry into the marginal zone [33]. Experimental analysis will be required to determine which, if any, of these hypotheses is correct.

New directions for neuronal migration Pearlman et aL

47

Figure 1 (b) R e e l e r

(a) Normal (+/+) MZ

SPP

CP SP

cP

IZ

IZ

VZ

vz

,, Current Opinion in Neurobiology

[ ~ - ] ECM components ~

Reelin

~ 0

Cortical plate neuron Radialglia

O

~

Migrating neuron Subplateneuron

Precursor cell O

Marginalzoneneuron

Normal and abnormal formation of the cortical plate in mouse. (a) In the stage of normal (+/+) neocortical development illustrated, the earliest cortical plate (CP) neurons (triangles) have moved into the preplate, dividing the two populations that form the preplate into the marginal zone (MZ) and subplate (SP). Subsequent cohorts of cortical plate neurons, generated in the ventricular zone (VZ) will move through the intermediate zone (IZ) along radial glia, then past their predecessors in the cortical plate, stopping when they reach the marginal zone. Several ECM components, including fibronectin, CSPGs, and hyaluronectin, are present in the preplate, and then in the marginal zone and subplate (grey shading). During normal development, reelin is only expressed in the marginal zone (diagonal hatching). (b) In the reeler mutant mouse, the cortical plate does not form within the preplate; instead, cortical neurons (triangles) accumulate beneath the undivided marginal zone and subplate neurons, which remain together in the superplate (SPP). CSPGs remain associated with superplate cells (grey shading) and reelin is absent,

F u n c t i o n a l role of reelin: e x p e r i m e n t a l analysis Analysis of the function of the reeler gene product began more than 25 years ago with the demonstration that normal dissociated cortical neurons reaggregate into clusters with some degree of lamination, whereas neurons from reeler cortex do not [42]. The first reagent to become available for examining the function of reelin, the CR-50 antibody [21,28"], causes abnormal reaggregation of dissociated wild-type cortical neurons that is similar to the abnormal reaggregation of dissociated reeler neurons [21,42]. The earliest cortical neurons of reeler adhere more readily to each other than do early wild-type neurons or later neurons of either genotype [23], supporting the hypothesis that the absence of reelin alters the adhesivity of early neurons [18,24]. Reelin is also involved in laver formation in the hippocampus and cerebellum, where it is produced by cells in the marginal zone. The CR-50 antibody, injected into the fetal lateral ventricle, disrupts hippocampal development in vivo [41°]. In the embryonic cerebellum, reelin is produced by very early cells present at the surface of the cerebellum when the first migrating Purkinje cells arrive [43]. In

the absence of reelin, Purkinje cells form clusters deep in the developing cerebellum rather than a well-ordered layer near the surface. Disruption of reelin function by CR-50 in explant cuhures inhibits the formation of a normal Purkinje cell layer, replicating the disorganized patterns found in explants of reeler cerebellum [44°]. This disruption is rescued, in part, by reelin-producing granule cells plated over the surface of the explants. Injections of reelin-producing granule cells into the cerebellar ventricular zone in vivo causes premigratory Purkinje cells to remain instead of migrating outward [44°]. These observations suggest that contact with reelin is necessary for forming a well-aligned Purkinje cell layer [44°], and are also compatible with the hypothesis that reelin is a stop signal for Purkinje cell migration [20,37]. Reelin is neither an alignment cue nor a stop signal for cerebellar granule cells (which produce reelin during their premigratory and migratory phases [43]), since they migrate into an explant enriched in reelin-producing marginal zone neurons [45°]. Both the experimental analysis with CR-50 and the distribution of reelin indicate that it may have roles that differ with location and maturational state. CR-50 interferes with the formation of connections between

48

Development

entorhinal cortex and hippocampus in explant co-cultures, indicating that reelin may be involved in the growth and targeting of these axons [46]. In early development, reelin is principally associated with cells in the cortical marginal zone, including the Cajal-Retzius neurons; however, in later stages, after migration is complete, it is expressed by cells in the cortical plate as well [33,34]. Reelin is produced in a variety of structures in the CNS, both in those that are abnormal in reeler and in others, such as the spinal cord and retina, in which abnormalities are not obvious [33,34]. It is also produced in the adult nervous system, and in a number of non-neural tissues that are histologically normal in reeler [24,26,33,34].

Mutations with a reeler-like phenotype Three independently discovered mutant mice with behavioral and histological features identical to reeler have all been found to have a mutation in the same gene. Both scrambler (scm) [47] and yotari O,ot) 148"1 have severely disrupted cortical, hippocampal and cerebellar lamination in early postnatal stages that are characteristic of reeler, and both produce rcelin normally [48"-50"]. Production of a targeted disruption of mdabl, one of two murine homologues of the Drosophila gene disabled, led to the remarkable finding that this mutation also has a ree/er-like phenotype [51"], and was instrumental in the identification of scrambler and yotari as alleles of mdabl [52"°,53"]. T h e product of mdabl is a cytoplasmic protein, m D a b l p80, with structural features indicative of an adapter protein that docks to other proteins through its phosphotyrosine residues and protein-interacting (PI/PTB) domain [51°'-53"°]. Thus, proteins that bind to m D a b l p80, such as nonreceptor tyrosine kinases Src, Abl, and Fyn, are probably involved in termination of migration and layer formation [54]. As mdabI is expressed by migrating cortical neurons that will make contact with reelin [51"°,52"'], the most attractive and parsimonious hypothesis at this stage is that m D a b l p80 is part of a signalling cascade that responds to reelin. Examination of early developmental stages in scrambler, yota~ and mdabl mutants will be necessary to eliminate the possibility that similar phenotypes have arisen from different developmental abnormalities. In addition, the prospect remains that m D a b l p80 is part of an independent pathway that is also involved in determining laminar position [51°°-53°°].

Other mutations affecting cortical lamination Mice lacking either the serine/threonine kinase cdk5 [55 °] or its neuron-specific regulatory partner p35 [56"] also have a severe disruption of cortical lamination, with a pattern that has interesting differences from ~eler. T h e preplate and marginal zone of mice lacking p35 contain reelin-producing Cajal-Retzius cells, and the preplatc is split normally by the arrival of the first cortical plate neurons. However, cell birthdating demonstrates that subsequent waves of cortical neurons accumulate within

and beneath the subplate, many remaining in the normally cell-sparse intermediate zone (YT Kwon, L-H Tsai, Soc Neurosd Abstr 1997, 23:75). These observations suggest that cdk5 and p35 are involved in the neuronal migratory machinery rather than at the final stages of migration that are disturbed in reeler, and that the migratow mechanisms of early- and late-generated neurons are different. The latter prospect is supported by the observation that early cortical neurons might move by nuclear translocation and retraction of the ventricular process rather than true locomotion [57], and that they do not produce the ECM component fibronectin, as do later populations [7]. T h e intriguing tish mutation in the rat produces a bandlike collection of heterotopic cortical neurons within the cortical white matter [58]. Cloning of the responsible gene will determine its relationship to human double cortex (sec below), which it resembles structurally.

Abnormalities in migration/lamination in human cortex More than 25 syndromes with abnormal neuronal migrations have been described in humans, and many have been shown to be genetic in origin [59,60]. Neuronal migration disorders (NMDs) primarily affect development of the cerebral cortex, but the extent and nature of the cortical malformation varies greatly. Characterization of the pathologic alterations and underlying defect in these syndromes will provide important biological cues towards understanding the role of specific cells and molecules in the formation of the cortex. Lissencephaly is a severe cortical malformation manifested by a smooth or minimally gyrated cerebral surface caused by incomplete neuronal migration [59]. It occurs as an isolated abnormality (isolated lissencephaly sequence; ILS) or in association with dysmorphic facial appearance in patients with Miller-Dicker lissencephaly [60]. The presence of a hemizygous chromosomal deletion at 17p13.3 in the majority of patients with Miller-Dicker lissencephaly led to identification of LIS-1 as the causative gene in this anomaly [61]. In at least 44% of patients with ILS, smaller deletions in this chromosomal region are found [60]. T h e LIS-1 gene contains WD40 repeats (-40 amino-acid-long sequences containing tryptophan-aspartic acid [W-D]), as seen in the 13 subunits of G proteins [61], and is a regulatory subunit of brain platelet-activating factor acetylhydrolase (PAF-AH), a G-protein-like trimer that regulates cellular levels of the lipid messenger platelet-activating factor (PAF) [62,63]. T h e importance of PAF-AH in the developing brain is supported by the high level of expression of mRNA transcripts for all three subunits during neuronal migratory epochs in cerebrum and cerebellum [64,65]. T h e LIS-1 gene product is prominent in Cajal-Retzius cells and ventricular neuroepithelium in developing human cortex [66], and a PAF receptor agonist decreases migration of cerebellar granule cells in vitro [67]. However, it remains to be

New directions for neuronal migration F'earlman et aL

understood how the absence of the LIS-1 gene product affects PAF-AH function, PAF signalling in the cell, and, ultimately, neuronal migration. In addition, LIS-1 may have as yet unidentified interactions in the cell, as suggested by the ability of the WD40 repeat segments of LIS-1 to interact with the cytoskeleton [68]. Zellweger syndrome is a severe, autosomal recessive NMD. It is a prototype for peroxisome biogenesis disorders in which the organelle is not correctly assembled, leading to multiple defects in peroxisome function and characteristic gyral abnormalities in the cerebral cortex, with a stereotypic medial pachygyria (reduced number of gyri, which are abnormally large) and lateral polymicrogyria (excess number of small gyri) [59,69]. Zellweger syndrome is a genetically heterogeneous disorder that may arise from defects in at least ten different genes [70]. Recently, two groups have provided the first animal model for a human N M D by targeted deletion in mice of genes encoding the PEX2 35kDa peroxisomal membrane protein [71"'] and the PEX5 peroxisomal protein import receptor [72"']. T h e s e mice provide important models for Zellweger syndrome and a major step toward deciphering the cellular mechanisms of this NMD. T h e r e are several tantalizing clues that suggest a mechanistic relationship between the neuronal migratory defects in Miller-Dieker lissencephaly and Zellweger syndrome. Mutations in homologues for the PEX2 gene [73] and the LIS-I gene [74] have been identified in filamentous fungi, and both cause abnormalities in processes involving nuclear migrations within the cell. Thus, these diverse gene mutations may similarly affect cellular mechanisms common to fungal nuclear migrations and the translocation of the neuronal cell soma along the radial glial fiber. Secondly, the glycero-ether linkage in PAF is essential for its biologic activity, and peroxisomes are necessary for the synthesis of ether phospholipids [69]. T h e synthesis of PAF by leukocytes was undetectable in two Zellweger patients studied at 3 and 4 weeks of age [75]. Thus, it will be important to further evaluate the PAF cellular levels and signalling pathways in developing neurons and glia in the context of these human N M D s and in available mouse models. Two distinct X-linked malformations of neuronal migration have been recently recognized in genetic linkage studies. T h e first is X-linked lissencephaly and subcortical band heterotopia (SBH), which consists of classical lissencephaly in hemizygous males and SBH in heterozygous females [76"]. In the less severe SBH (also called 'double cortex' syndrome), there are bilateral bands of disorganized gray matter located just beneath the cortex and separated from it by a thin band of white matter. These disorders are caused by mutation of a single gene, X L I S [76°]. T h e second X-linked malformation syndrome is bilateral periventricular nodular heterotopia (BPNH), which consists of B P N H in females and prenatal lethality

49

or a more severe phenotype in males. In this disorder, large masses of well-differentiated cortical neurons fill the adult subependymal zone [77"°]. T h e gene for B P N H has been mapped by linkage analysis to Xq28 [77°°,78]. T a n g e n t i a l m i g r a t i o n s in n e o c o r t i c a l development

Although the majority of cortical neurons migrate along radial gila, radial migration does not account for the significant tangential dispersion of clonally related cortical neurons [1,2]. Both postmitotic neurons and progenitors may contribute to this dispersion (Figure 2): first, a significant proportion of postmitotic neurons generated in the ventricular zone (VZ) migrate tangentially within the intermediate zone (IZ) [79]; second, tangentially oriented, postmitotic neurons are present within the VZ and subventricular zone (SVZ) [80,81] and can migrate long distances within these regions [81]; third, neuronal precursors also move tangentially within the VZ [82,83]; finally, a population of neurons moves tangentially into neocortex from proliferative zones that are actually outside the neocortex. Long tangential migrations are a prominent developmental feature in both the cerebellum and the olfactory, bulb. In the cerebellum, neuronal precursors move tangentially from the rhombic lip to form the external granular layer. As the olfactory bulb forms, future interneurons are generated in the telencephalic SVZ and migrate into the bulb in a long tangential pathway [84,85]. T h e migration is dependent on polysialated N-CAM (neural cell adhesion molecule) and is guided, in part, by negative chemotropism [86,87]. T h e SVZ-derived neurons move rapidly along one another in unique chain formations independent of radial glia or axonal processes, in a migration that persists into adulthood [88,89*',90]. Substantial evidence suggests that a tangential in-migration of neurons also plays an important role in the normal development of the neocortical marginal zone (MZ). T h e embryonic MZ is a complex network of neurons, neuronal and radial glial processes, and ECM [37,91] that is essential for the orderly formation of subsequent cortical layers [19]. In the human fetal MZ, there are two transient populations of pleiomorphic cells: the fetal Cajal-Retzius neurons, which are the first to appear in the preplate [92J, and the neurons of the subpial granule cell layer (SGL), which appear later, after both the first Cajal-Retzius cells and the early cortical plate neurons have arrived. Morphological evidence indicates that SGL cells originate as an extension of a proliferative SVZ located in the frontal pole, just behind the olfactory bulb. T h e y appear to move from this SVZ to the subpial layer, then migrate tangentially in the MZ across the entire cortex [93]. Similar observations in the developing rodent brain also suggest a tangential migration of neurons from the olfactory SVZ into the forming MZ. In the embryonic rat, a large cohort of early-generated cells is concentrated adjacent to the

50

Development

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(b)

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Current Opinion in Neurobiology

Tangential migrations of cortical neurons. (a) A coronal section of the early murine telencephalic vesicle. Postmitotic GABAergic neurons move from the forming striatum into the MZ and IZ of neocortex (long arrows). Neurons move from the proliferative VZ and SVZ of the LGE into the forming striatum (short arrows); it is not yet clear whether all neurons destined for the cortex traverse the striatum or move directly into cortex from the proliferative zones. In addition, neurons may also move tangentially into the MZ from a SVZ near the olfactory bulb (not shown). (b) An enlarged portion of the dorsal neocortex. In addition to the well-known glial-guided migration that moves neurons radially from the VZ to the cortical plate (cell labeled 1), precursor cells migrate tangentially in the VZ (cell labeled 2), and postmitotic neurons move tangentially in the VZ, SVZ and IZ (cell labeled 3).

olfactory ventricle; it later extends subpially along the rostrocaudal axis in the MZ of olfactory (pyriform) cortex and encroaches on the MZ of neocortex [94,95"*]. Experimental evidence directly demonstrates that earlyborn neurons invade the neocortical MZ from the lateral ganglionic eminence (LGE) and developing striatum ([95",96°']; JE Brunstrom, MR Gray-Swain, AL Pearlman, Soc Neurosci Abstr 1997, 23:80). These regions supply a tangentially migrating cohort of GABAergic neurons [97] to the neocortical IZ as well [96°°,98°]. T h e number of GABAergic neurons throughout the neocortex is dramatically reduced by separating the neocortex from the underlying LGE/striatum during early embryonic development, suggesting that the L G E is a major source of neocortical interneurons [96°°]. This migration is disrupted in the absence of the transcription factors Dlxl and Dlx2 [96 °°] and may be regulated by neurotrophins. Exogenous application of neurotrophin-4 (NT4) causes a dramatic increase in the number of early-generated

neurons throughout the MZ that is most prominent in anterior and lateral neocortex [99"]. T h e excess neurons that accumulate after addition of N T 4 are GABAergic and distinct from Cajal-Retzius neurons. They are morphologically similar to the SGL cells of the developing human MZ ([93]; G Meyer, A Goffinet, Soc Neurosd Abstr 1997, 23:80), and like human SGL neurons, they continue to accumulate in the MZ even after the cortical plate has formed (JE Brunstrom, MR Gray-Swain, AL Pearlman, Soc Neurosci Abstr 1997, 23:80).

Conclusions Forward and reverse genetic analysis of mutant mice has led to important new discoveries regarding the molecular mechanisms that underlie neuronal migration and layer formation in the cerebral and cerebellar cortices. Defects in lamination in the human cortex, a significant cause of epilepsy and mental retardation, are frequently genetic; the cloning of a few of the responsible genes has provided new possibilities for producing models of these disorders

New directions for neuronal migration Pearlman et al.

that can be analyzed in mice. The tangential migrations that take place within the cortex, and those that originate in quite distant locations, provide important additions to the well established, glial-guided radial migration that moves many cortical neurons to their permanent location. Tangential migrations also provide new challenges for understanding the anatomical and molecular substrata that guide them.

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Bar I, Lambert de Rouvroit C, Royaux I, Krizman DB, Dernoncourt C, Ruelle D, Beckers MC, Goffinet AM: A YAC contig containing the reeler locus with preliminary characterization of candidate gene fragments. Genomics 1995, 26:543-549.

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Hirotsune S, Takahara T, Sasaki N, Hirose K, Yoshiki A, Ohashi T, Kusakabe M, Murakami Y, Muramatsu M, Watanabe S e t aL: The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons. Nat Genet 1995, 10:77-83.

27.

Royaux I, Lambert de Rouvroit C, D'Arcangelo G, Demirov D, Goffinet AM: Genomic organization of the mouse reelin gene. Genomics 1997, 46:240-250.

8. •*

Rio C, Rieff HI, Qi PM, Corfas G: Neuregulin and erbB receptors play a critical role in neuronal migration. Neuron 1997, 19:3950. Demonstrates that cerebellar granule cells express neuregulin (NRG) and that Bergman gila express the receptor tyrosine kinase erbB4. Antibody blockade of erbB4 blocks the conversion of cultured 91ial cells to a radial morphology that occurs when either neurons or NRG are added. In addition, dissociated radial glial cells expressing a dominant-negative erbB4 do not support the migration of cerebellar granule cells. 9. •,

Anton ES, Marchionni MA, Lee KF, Rakic P: Role of GGF/Neuregulin signaling in interactions between migrating neurons and radial gila in the developing cerebral cortex. Development 199"7, 124:3501-3510. This paper used a neuregulin, glial growth factor 2 (GGF2), and functionblocking antibodies to demonstrate that GGF2 promotes migration of cortical neurons in elegant cortical imprint cultures and growth of radial glial processes. GGF2 is expressed by migrating neurons and cortical plate cells; a neuregulin receptor, erbB2, is expressed by radial gila, whereas neurons express erbB3 and erbB4. GGF2's effects may be mediated by a brain lipid-binding protein. 10. •,

Zheng C, Heintz N, Hatten ME: CNS gene encoding astrotactin, which supports neuronal migration along glial fibers. Science 1996, 272:417-419. Molecular cloning of astrotactin (ASTN), a neuronal protein that functions in adhesion to glial cells, and, specifically, in neuronal locomotion of immature neurons atong astroglial fibers. The gene encoding ASTN predicts a protein structure with three epidermal growth factor repeats and two fibronectin type III repeats. Astrotactin mRNA is expressed in postmitotic neurons undergoing migration in cortical regions of developing brain. Functional studies of the expressed protein demonstrate that antibodies against recombinant ASTN peptide block neuronal migration along glial fibers. This suggests that ASTN is a principal ligand for the directed migration of young neurons along the glial fiber system.

28. •

D'Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T: Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. J Neurosci 1997, 17:23-31. A clear demonstration that reelin is secreted by COS cells expressing a full-length transcript, and by cerebellar explants. Also demonstrates that an epitope near the amino terminus of reelin is recognized by the CR-50 antibody, an important step in establishing the utility of this antibody. 29.

De Bergeyck V, Nakajima K, Lambert de Rouvroit C, Naerhuyzen B, Goffinet A, Ogawa M, Mikoshiba K: A truncated Reelin protein is produced but not secreted in the "Orleans" reeler mutation (Re|nrl'Orl). Mol Brain Res 199?, 50:85-90.

30.

Royaux I, Bernier B, Montgomery JC, Flaherty L, Goffinet AM: Reln(RI-AIb2), an allele of reeler isolated from a chlorambucil

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Ikeda Y, Terashima T: Corticospinal tract neurons are radially malpositioned in the sensory-motor cortex of the shaking rat Kawasaki. J Comp Neuro/1997, 383:370-380.

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DeSilva U, D'Arcangelo G, Braden VV, Miao GG, Curran T, Green ED: The human reelin gone-isolation, sequencing, and mapping on chromosome 7, Genome Res 1997, 7:157-164.

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Schiffmann SN, Bernier B, Goffinet AM: Reelin mRNA expression during mouse brain development, Eur J Neurosci 1997, 9:10551071.

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Ikeda Y, Terashima T: Expression of reelin, the gone responsible for the reeler mutant, during mouse embryonic development and in adulthood. Dev Dyn 1997, 210:157-1 ?2.

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Miller B, Sheppard AM, Bicknese AR, Pearlman AL: Chondroitin sulfate proteoglycans in the developing cerebral cortex: the distribution of neurocan distinguishes forming afferent and efferent axonal pathways. J Comp Neurol 1995, 355:615-628.

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Meyer-Puttlitz B, Junker E, Margolis RU, Margolis RK: Chondroitin sulfate proteoglycans in the developing central nervous system. II. Immunocytochemical localization of neurocan and phosphacan. J Comp Neuro11996, 366:44-54.

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Pearlman AL, Sheppard AM: Extracellular matrix in early cortical development. In Neural Development and Plasticity. Progress Brain Research. Edited by Mize RR, Erzurumlu R. Amsterdam: Elsevier; 1996:119-134.

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47.

Sweet HO, Bronson RT, Johnson KR, Cook SA, Davisson MT: Scrambler, a new neurological mutation of the mouse with abnormalities of neuronal migration. Mamm Genome 1996, 7:798-802.

48. •

Yonishema H, Nagata E, Matsumoto M, Yamada M, Nakajima K, Miyata T, Ogawa M, Mikoshiba K: A novel neurological mutation of mouse, yotari, which exhibits reeler-like phenotype but expresses reelin. Neurosci Res 1997, 29:217-223. Clear demonstration that a new mutation in mouse has the same cortical and cerebellar phenotype as reeler, but is not allelic to reelin and produces reelin. Also demonstrates that the defect is not attributable to an absence of cdk5, p35, or PAF-AH. 49. •

Gonzalez JL, Goldowitz D, Sweet HO, Davisson MT, Walsh CA: Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype. J Neurosci 199'7, 17:9204-9211. A careful analysis of neocortex and hippocampus in scrambler, demonstrating that both the morphology and the distribution of cell-birthdate cohorts are identical to reeler, thus suggesting that the scrambler gone product acts downstream of reeler. 50. •

Goldowitz D, Cushing R, Laywell E, D'Arcangelo G, Sheldon M, Sweet H, Davisson M, Steindler D, Curran T: Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of Reelin. J Neurosci 1997, 17:87678777. A careful analysis of the cerebellum of scrambler, demonstrating that it is nearly identical to that of reeler, but that reelin is expressed normally, thus placing the action of the scrambler gone product either downstream of reelin or in an independent pathway.

Frantz GD, McConnell SK: Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 1996, 17:55-61. ~na series of very difficult experiments, the authors demonstrate that late cortical neuronal progenitors continue to produce upper-layer neurons when transplanted into young cortex, where host progenitors are producing deeplayer neurons. Thus, although prior experiments had shown that early progenitors are capable of responding to environmental cues to produce upper-layer neurons when transplanted to late cortex, this study shows that late progenitors have lost the capability of producing deep-layer neurons.

Howell BW, Hawkes R, Soriano P, Cooper JA: Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 1997, 389:733-737. This paper demonstrates that targeted disruption of mdabl produces the reeler phenotype, that the gene's protein product, mDabl p80, is expressed in migrating cortical neurons, and that reelin is expressed normally in the knockout. The findings were critical in the identification of scrambler and yotari as alleles of mdabl (see [52"°,53"]).

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Rakic P, Caviness VS Jr: Cortical development: view from neurological mutants two decades later. Neuron 1995, 14:1101-1104.

52. ••

40.

Goffinet AM: A real gone for reeler. Nature 1995, 374:6?5-676.

41. •

Nakajima K, Mikoshiba K, Miyata T, Kudo C, Ogawa M: Disruption of hippocampal development in vivo by CR-50 mAb against reelin. Proc Nat/Acad Sol USA 1997, 94:8196-8201. An important demonstration that the CR-50 monoclonal antibody interferes with the function of reelin in vivo. 42.

DeLong GR, Sidman RL: Alignment defect of reaggregating cells in cultures of developing brains of reeler mutant mice. Dev Bio11970, 22:54-60.

43.

Miyata T, Nakajima K, Aruga J, Takahashi S, Ikenaka K, Mikoshiba K, Ogawa M: Distribution of a reeler gonerelated antigen in the developing cerebellum: an immunohistochemical study with an allogeneic antibody CR-50 on normal and reeler mice. J Comp Neuro/1996, 372:215-228.

44. •

Miyata T, Nakajima K, Mikoshiba K, Ogawa M: Regulation of Purkinje cell alignment by reelin as revealed with CR-5O antibody. J Neurosci 1997, 17:3599-3609. An important step in the experimental analysis of reelin function, demonstrating that the reeler phenotype is replicated in cerebellar explant cultures by the CR-50 antibody and rescued, in part, by reelin-producing cerebellar granule cells. 45. •

Soriano E, Alvarado-Mallart RM, Dumesnil N, Del Rio JA, Sotelo C: CajaI-Retzius cells regulate the radial gila phenotype in the adult and developing cerebellum and alter granule cell migration, Neuron 1997, 18:563-577. A creative use of transgenic mice expressing markers for particular cell types, demonstrating that cells of the cortical marginal zone express a diffusible factor (not reelin) that causes mature cerebellar Bergman 91ia to express a juvenile phenotypic marker. Also demonstrates that immature Bergman gila extend processes into the marginal zone explant, and that cerebellar granule celts migrate into it, in the direction opposite their normal migration. Raises the intriguing prospect that cells of the marginal zone may produce a tropic factor for glial growth or neuronal migration. 46.

Del Rio JA, Heimrich B, Borrell V, Forster E, Drakew A, Alcantara S, Nakajima K, Miyata "1, Ogawa M, Mikoshiba K et aL: A role for CajaI-Retzius cells and reelin in the development of hippocampal connections. Nature 1997, 385:70-74.

51. •o

Sheldon M, Rice DS, D'Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, Howell BW, Cooper JA, Goldowitz D, Curran T: Scrambler and yotari disrupt the disabled gone and produce a reeler-like phenotype in mice. Nature 1997, 389:730-733. Demonstrates that scrambler and yotari are alleles of mdabl, that both express mutant forms of mdabl mRNA, and the mRNA is expressed in migrating cortical neurons that will come in contact with reelin. See also [51 "',53"']. 53. ••

Ware ML, Fox JW, Gonzalez JL, Davis NM, Derouvroit CL, Russo C J, Chua SC, Goffinet AM, Walsh CA: Aberrant splicing of a mouse disabled homolog, mdabl, in the scrambler mouse. Neuron 1997, 19:239-249. Demonstrates that mdabl transcripts are abnormally spliced in scrambler, indicating that mdabl is the scrambler gone. See also [51 " , 5 2 " ] . 54.

Howell BW, Gertler FB, Cooper JA: Mouse disabled ( m D a b l ) - a Src binding protein implicated in neuronal developmenL EMBO J 1997, 16:121-132.

55. •

Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, Brady RO, Martin U, Kulkarni AB: Targeted disruption of the cyclin-dependent kinase 5 gone results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Nail Acad Sci USA 1996. 93:111 73-11178. An important demonstration that targeted disruption of the gone for cyclindependent kinase 5 (cdk5) produces abnormal lamination of cerebral and cerebellar cortices. 56. •

Chae T, Kwon YT, Bronson R, Dikkes P, Li E, Tsai LH: Mice lacking p35, a neuronal specific activator of cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 1997, 18:29-42. This paper reports that targeted disruption of p35, a neuron-specific activator of cdk5, produces abnormalities in cortical lamination, thus clearly implicating the cdk5/p35 complex in neuronal migration. The defects of mice lacking p35 are less severe than those lacking cdk5. suggesting that there may be other regulatory partners for cdk5. 57.

Brittis PA, Meiri K, Dent E, Silver J: The earliest pattern of neuronal differentiation and migration in the mammalian central nervous system. Exp Neurol 1995, 133:1-12.

58.

Lee KS, Schottler F, Collins JL Lanzino G, Couture D, Rao A, Hiramatsu K, Goto Y, Hong SC, Caner H et al.: A genetic animal model of human neocortical heterotopia associated with seizures. J Neurosci 199?, 17:6236-6242.

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Hattori M, Adachi H, Tsujimoto M, Arai H, Inoue K: Miller-Dieker lissencephaly gene encodes a subunit of brain plateletactivating factor acetylhydrolase. Nature 1994, 370:216-218.

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Ho YS, Swenson L, Derewenda U, Serre L, Wet YY, Dauter Z, Hattori M, Adachi T, Aoki J, Arai H e t aL: Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. Nature 1997, 385:89-93.

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ReinerO, Albrecht U, Gordon M, Chianese KA, Wong C, GalGerber O, Sapir T, Siracusa LD, Buchberg AM, Caskey CT et al.: Lissencephaly gene (LIS1) expression in the CNS suggests a role in neuronal migration. J Neurosci 1995, 15:3,730-3738.

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Xiang X, Osmani AH, Osmani SA, Xin M, Morris NR: NudF, a nuclear migration gene in Aspergillus nidulans, is similar to the human LIS-1 gene required for neuronal migration. Mol B/o/Ceil 1995, 6:297-310.

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Sturk A, Schaap MCL, Prins A, ten Care JW, Govaerts LOP, Wanders RJA, Heymans HSA, Schutgens RBH: Age-related deficiency of the synthesis of platelet activating factor by leukocytes from Zellweger patients. Blood 1987, 70:460-463.

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Ross ME, Allen KM, Srivastava AK, Featherstone 1", Gleeson JG, Hirsch B, Harding BN, Andermann E, Abdullah R, Berg M e t al.: Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): agene causing neuronal migration defects in human brain. Hum Mol Genet 199'7, 6:555-562. X-linked lissencephaly and subcortical band heterotopia (SBH) are caused by mutation of a single gone. Using linkage analysis in five families, the XLIS gone has been mapped to Xq21-q24. The authors describe physical mapping of a balanced X ; 2 translocation (i.e. a translocation of chromosomal material between chromosomes 2 and X) in a girl with lissencephaly that further narrows the candidate genetic locus to Xq22.3-q23. 7'7. ==

Eksioglu YZ, Scheffer IE, Carclenas P, Knoll J, Dimario F, Ramsby G, Berg M, Kamuro K, Berkovic SF, Duyk GM et aL: Periventricular heterotopia-an X-linked dominant epilepsy locus causing aberrant cerebral cortical developmenL Neuron 1996, 16:,77-87. This paper combines genetic mapping, magnetic resonance imaging, and pathologic analysis to define the epilepsy syndrome bilateral periventricular nodular heterotopia (BPNH) in four pedigrees. The authors identified a genetic locus at Xq28 that is linked to this disorder. Because of the presence of different neuronal types in different nodules, they suggest that the BPNH gene may be involved in proliferation of neuronal precursor cells, with loss of function resulting in formation of excessive numbers of cortical neurons that do not migrate properly.

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Albrecht U, Abu-lssa R, Ratz B, Hator M, Aoki J, Arai H, Inoue K, Eichele G: Platelet-activating factor acetylhydrolase expression and activity suggest a link between neuronal migration and platelet-activating factor, Dev Biol 1996, 180:579-593.

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Clark GD, Mizguchi M, Antalffy B, Barnes J, Armstrong D: Predominant localization of the Its family of gene products to CajaI-Retzius cells and ventricular neuroepithelium in the developing human cortex. J Neuropathol Exp Neuro11997, 56:1044-1052.

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Bix GJ, Clark GD: Platelet-activating factor receptor stimulation disrupts neuronal migration in vitro. J Neurosci 1998, 18:307318.

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Wang DS, Shaw R, Hattori M, Arai H, Inoue K, Shaw G: Binding of pleckstrin homology domains to WD40/beta-transducin repeat containing segments of the protein product of the Lis-1 gone. Biochem Biophys Res Commun 1995, 209:622-629.

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Lazarow PB, Moser HW: Disorders of peroxisome biogenesis. In The Metabolic and Molecular Basis of Inherited Disease. Edited by Scriver CR, Beaudet AL, Sly WS, Valle D. New York: McGraw Hill; 1994:2287-2324.

MenezesJR, Luskin MB: Expression of neuron-specific tubulin defines a novel population in the proliferative layers of the developing telencephalon. J Neurosci 1994, 14:5399-5416.

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FishellG, Mason CA, Hatten ME: Dispersion of neural progenitors within the germinal zones of the forebrain. Nature 1993, 362:636-638.

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Reid CB, Liang I, Walsh C: Systematic widespread clonal organization in cerebral cortex. Neuron 1995, 15:299-310.

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LuskinMB: Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 1993, 11:1,73-189.

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Zigova T, Betarbet R, Soteres BJ, Brock S, Bakay RAE, Luskin MB: A comparison of the patterns of migration and the destinations of homotopically transplanted neonatal subventricular zone cells and heterotopically transplanted telencephalic ventricular zone cells. Dev Bio11996, 173:459-474.

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Hu H, Rutishauser U: A septum-derived chemorepulsive factor for migrating olfactory interneuron precursors. Neuron 1996, 16:933-940.

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Hu H, Tomasiewics H, Magnuson T, Rutishauser U: The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 1996, 16:735743.

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Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, Chen G, Raymond G, Liu A, Gordon Det aL: Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr 1995, 127:1322.

71. °,,

FaustPL, Hatten ME: Targeted deletion of the pex2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder. J Ceil Biol 1997, 139:1293-1306. By using gene targeting in embryonic stem cells, the authors created a mouse model for Zellweger syndrome by deleting the gene encoding PEX2 peroxisomal integral membrane protein. These mice displayed intrauterine growth retardation, were severely hypotonic at birth and died within 12 hours. The mutant mice lack normal peroxisomes and display characteristic peroxisomal biochemical abnormalities. In the CNS of newborn mutant mice, there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. See also Baes eta/. [72"°]. 72. •*

Baes M, Gressens P, Baumgart E, Carmeliet P, Casteels M, Fransen M, Evrard P, Fahimi D, Declercq PE, Collen D et al.: A mouse model for Zellweger syndrome. Nat Genet 1997, 17:4957. By using gone targeting in embryonic stem cells, the authors created a mouse model for Zellweger syndrome by inactivating the PEX5 gene that encodes the PTS-1 import receptor for most peroxisomal proteins. These mice displayed intrauterine growth retardation, were severely hypotonic at birth and died within '72 hours. The mutant mice lacked normal peroxisomes and displayed characteristic peroxisomal biochemical abnormalities. Analysis of the neocortex revealed impaired neuronal migration and maturation, as well as extensive apoptotic death of neurons. See also Faust and Hatten [71 "]. 73.

Berteaux-Lecellier V, Picard M, Thompson-Coffe C, Zickler D, Panvier-Adoutte A, Simonet J-M: A nonmammalian homolog of

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Wichterle H, Garcia-Verdugo JM, Alvarez-Buylla A: Direct evidence for homotypic, gila-independent neuronal migration. Neuron 1997, 18:779-791. Demonstrates that migrating neurons from the SVZ use one another, not gila or accessory cells, as guides during postnatal migration into the olfactory bulb; this chain migration (see [88]) is characteristic of SVZ precursors and not precursors from neocortical VZ or cerebellar proliferative zones.

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Gadisseux J-F, Goffinet AM, Lyon G, Evrard P: The human transient subpial granular layer: an optical, immunohistochemical, and ultrastructural analysis. J Comp Neurol 1992, 324:94-114.

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Valverde F, Santacana M: Development and early postnatal maturation of the primary olfactory cortex. Dev Brain Res 1994, 80:96-114.

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De Carlos JA, Lopez-Mascaraque L, Valverde F: Dynamics of cell migration from the lateral ganglionic eminence in the rat. J Neurosci 1996, 16:6146-6156. With difficult dye injections in whole-embryo cultures, the authors demonstrate that early-generated neurons from the LGE form the primary olfactory cortex. The paper also provides the first evidence that neurons cross the certieostriatal boundary from the LGE into the neocortical preplate.

96. *.

Anderson SA, Eisenstat DD, Shi L, Rubenstein JLR: Intarneuron migration from basal forebrain to neocortex: dependence on D/x genes. Science 1997, 278:474-476. Demonstrates in organotypic slice-cultures that GABAergic neurons generated in the LGE migrate across the corticostriatal boundary into the MZ and IZ of the neocortex, and that this migration does not occur when both Dlxl and DIx2 are absent. This work directly challenges the notion that the neocortex arises solely from the neocortical VZ, and raises the intriguing possibility that the LGE supplies the majority of neocortical interneurons. 97.

DeDiego I, Smith-Fernandez A, Fairen A: Cortical cells that migrate beyond area boundaries: characterization of an early neuronal population in the lower intermediate zone of prenatal rats. Eur J Neurosci 1994, 6:983-997.

98. •

Tamamaki N, Fujimori KE, Takauji R: Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J Neurosci 1997, 17:8313-8323. This paper demonstrates that the tangentially migrating neurons in the neocortical IZ are generated early and that, in vitro and in rive, most of these neurons originate in the LGE. 99. -.

Brunstrom JE, Gray-Swain MR, Osborne PA, Pearlman AL: Neuronal heterotopias in the developing cerebral cortex produced by neurotrophin-4. Neuron 1997, 18:505-517. Demonstrates that exogenously applied NT4 induces a dramatic increase in the number of neurons in the neocortical MZ, both in organotypic slices and in vivo. NT4 does not rescue cortical neurons from cell death or cause them to proliferate, indicating that, in the presence of NT4, early-generated neurons migrate into the MZ from regions outside the neocortex.