Trends in Neurosciences
Volume 23, Issue 8, 1 August 2000, Pages 352-359
Journal home page for Trends in Neurosciences

Review
Neuronal migration disorders: from genetic diseases to developmental mechanisms

https://doi.org/10.1016/S0166-2236(00)01607-6Get rights and content

Abstract

Neurons that constitute the cerebral cortex must migrate hundreds of cell-body distances from their place of birth, and through several anatomical boundaries, to reach their final position within the correct cortical layer. Human neurological conditions associated with abnormal neuronal migration, together with spontaneous and engineered mouse mutants, define at least four distinct steps in cortical neuronal migration. Many of the genes that control neuronal migration have strong genetic or biochemical links to the cytoskeleton, suggesting that the field of neuronal migration might be closing in on the underlying cytoskeletal events.

Section snippets

Neuronal migration onset: periventricular heterotopia and filamin 1

Neurons are born in the ventricular zone (also known as the proliferative zone or germinal matrix) of the telencephalon. Once a postmitotic neuron is generated, it must migrate away from the ventricular zone towards the developing cortical plate. In the human disorder periventricular heterotopia (PH), a fraction of newly postmitotic neurons appears incapable of leaving the ventricular zone. In the adult, one population of differentiated neurons is present as clumps or nodules along the lining

The ongoing process of migration: lissencephaly, double cortex, LIS1 and doublecortin

After neurons exit the ventricular zone, they must migrate long distances towards the cortical plate. This ongoing process of migration appears to be abnormal in two other disorders in which neurons do not remain in the ventricular zone, but instead are capable of migrating partway to the cerebral cortex before arresting24. One such disorder in humans is ‘type I’ lissencephaly (literally, smooth brain, which refers to the smoothening of the contour of the cortex that results from its

Penetration of migrating neurons through the subplate: the reeler and scrambler mice; Reelin, Dab1, Vldlr and Apoer2

As neurons complete their migration they become organized into the cortical plate in patterns that presage the adult layers. This final stage of migration has been the subject of intense investigation recently. The reeler mouse shows a rough inversion of the normal inside-out pattern of cortical migration, and an excess of neurons in the normally cell-sparse marginal zone (layer 1) (Fig. 4a,b,c; Ref. 9). The primary defect in reeler seems to be that cortical plate neurons do not insert into the

Multiple roles of Cdk5 and its activator, p35

Mutations in two other genes, which encode Cdk5 (cyclin-dependent kinase 5) and its regulator, p35 (also known as Cdk5r2), also disrupt migration, although the precise stage at which these proteins is required is a bit more complicated. Like reeler, the Cdk5 and p35 engineered mutations produce phenotypes in mice with an inverted cortical plate. However, these mutants are not identical to the reeler phenotype, as they leave the marginal zone intact and do not severely disrupt the accuracy with

Type-II lissencephalies disrupt cortical architecture by effacing the pial limiting membrane of the cortex

A number of disorders both in mice and humans appear to disrupt the architecture of the developing cerebral wall, and these conditions are also associated with severe disruptions of neuronal migration. In humans, disorders referred to collectively as ‘type-II lissencephaly’ produce a smooth brain (as in type-I lissencephaly) but rents are formed in the pial surface allowing the migration of neurons out of the CNS and onto the overlying subarachnoid tissue. Recessive type-II lissencephaly in

Potential connections between mouse and human neuronal migration defects

Is there any evidence that either the genes that cause neuronal migration defects in mice also lead to defects in human disorders of migration, or that the mouse and human genes associated with neuronal migration will interact genetically or physically? Although there are not yet any definitive connections, there are some hints that there will be convergence of mouse and human disorders of neuronal migration in the future. Human lissencephaly and the cortical defect in the Cdk5 and p35

Concluding remarks

Genetic analysis of migration mutants suggests that cortical neuronal migration can be divided into at least four discrete events and potentially more (see Fig. 1). PH and the associated mutation in FLN1 suggest that the onset of migration comprises a distinct event, and the strong interaction between FLN1 and actin suggests that this event might depend on actin-mediated mechanisms. Lissencephaly and double cortex appear to be caused by defects in the ongoing process of migration; the strong

Acknowledgements

Research in the laboratory of J.G.G. is supported by the NIH Neurological Sciences Academic Development Award 5K12NS01701-05, from a Junior Investigator Grant from the Epilepsy Foundation and by the Searle Scholars Program. Research in the laboratory of C.A.W. is supported by the NIH through grants RO1 NS38097, RO1 NS35129, RO1 NS32457 and PO1 NS38289; by the National Alliance for Autism Research; and the National Alliance for Research in Schizophrenia and Depression. The authors’ thank J.

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