ReviewPotential mechanisms of mutations that affect neuronal migration in man and mouse
Introduction
The long-range migration of neurons in the developing brain is a process that is unusually amenable to genetic analysis, so that the past two years have witnessed a small explosion in our understanding. During development, neurons are generated in specialized proliferative zones along the ventricular cavities, called ventricular zones (VZs). Postmitotic neurons then migrate through the parenchyma over variable distances before they settle and form early architectonic patterns. Although neuronal migration occurs throughout the nervous system, it is best known and studied in the cerebral cortex, the hippocampus, the olfactory bulb, and the cerebellar cortex.
The most familiar type of neuronal migration proceeds radially from the VZs to the pial surface. The leading process — which represents the dendritic tip that will become the dendritic pole — as well as the cell body and the trailing process are all closely apposed to and follow radial neuroepithelial and, later, glial fibers. Thus this migration has been termed giophilic [1]. More recently, the known variety of tangential migration, parallel to the pial surface, has been greatly expanded. Examples are the migration of external cerebellar granule cells [2], or of γ amino butyric acid (GABA)ergic neurons from the ganglionic eminence to the cortex 3, 4, 5. In tangential migrations, the leading process is capped with a growth cone that is similar to axonal growth cones and migration proceeds perpendicularly to the radial fibers, often, though not always, in apposition to other neurons; hence, it is sometimes called neuronophilic. More recently, a third type of neuronal migration, called chain migration, has been introduced to describe migration from the subventricular zones to the olfactory bulb and rostral forebrain 5, 6. Neurons appear to move within a glial tunnel and their leading processes have features of growth cones [7]. How chain migration differs from gliophilic and neuronophilic migration remains to be assessed. This review discusses recent progress in the understanding of genes that are required for neuronal migration, and our attempts to fit these genes into biochemical and cellular pathways.
Section snippets
Events in neuronal migration
Studies of migrating cells in culture [8], define three main events: first, migration is initiated at the cell’s leading edge through formation of protrusions and formation of adhesion plaques; this is controlled by GTPases of the Rho family, such as Cdc42 and Rac, that regulate the polymerization and reorganization of actin microfilaments; second, contractile forces behind the leading edge drive movement of the cell body, particularly displacement of the nucleus (nucleokinesis), there is
Potential disorders of actin and leading processes
Human X-linked periventricular heterotopia is a disorder of radial migration that results in the formation of islands of ectopic neurons that stay close to the ventricle 12, 13. It is caused by mutations in the gene encoding filamin-1 (FLN1; also known as FLNA and actin binding protein 280 [ABP-280]), which encodes an actin-cross-linking phosphoprotein that transduces ligand–receptor binding into actin reorganization, and is required for locomotion of many cell types [14], and for filopodia
Potential disorders of microtubules
Reorganization of the microtubule network of a cell is also crucial for migration and two genetic migratory disorders in humans have been indirectly linked to aspects of microtubule function. In man, heterozygous mutation or deletion of the gene encoding the β subunit of platelet-activating factor acetylhydrolase (PAFAH1β1, also known as LIS1) is associated with type I lissencephaly of the Miller-Dieker type [15]. Mice with one inactive Lis1 allele display cortical, hippocampal and olfactory
Cdk5 may regulate both actin and microtubules
Although cyclin-dependent kinase (Cdk)5 is structurally homologous to other Cdks, it is unique in functioning primarily in postmitotic neurons and may represent a link between actin and microtubules in migrating neurons. In Cdk5−/− mice, there are widespread deficits of migration in several parts of the brain, including the cerebral cortex, hippocampus, cerebellum and brainstem, as well as axonal alterations, particularly in brainstem 28, 29. Cdk5 is activated by a co-factor called p35, and the
Antimigratory genes of the Reelin family may inhibit both actin and microtubules
Regarding neuronal migration as leading-edge extension plus displacement of the nucleus may also help explain the action of the Reelin pathway — mutations of the genes encoding this pathway generate the reeler phenotype in mice [35]. The reeler mice have defective organization of neuronal cell patterns that reflects defects at the very end stages of radial migration. Reelin is a secreted extracellular matrix glycoprotein. In the embryonic brain, it is made by some neurons in the marginal zone
Conclusions
Studies of man and mouse mutations converge with previous work in less complex organisms and point to the importance of the actin and microtubule cytoskeleton in the regulation of neuronal migration. We speculate that the mechanisms involved are best understood by considering that neuronal migration is not solely extension at the leading edge but also displacement of the nucleus, and that both phenomena are controlled individually. Further studies are needed to evaluate that hypothesis.
Acknowledgements
We wish to thank N Ronald Morris and Sigrid Reinsch for discussion. Chrisopher Walsh is supported by National Institutes of Health grants RO1 NS38097, RO1 NS35129, RO1 NS32457, and PO1 NS38289, and by the National Alliance for Autism Research and the National Alliance for Research in Schizophrenia and Depression. André Goffinet is supported by grants Fonds de la Recherche Scientifique 3.4533.95, Actions de la Recherches Concertées 94/99-186, and the Fondation Médicale Reine Elisabeth.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
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