Determinants of nerve cell patterns during development: a review.

The aim of the work reviewed is to define some of the mechanisms which are implicated in the control of neural cell pattern formation in the developing central nervous system. This question was examined by studies of brain embryonic development in normal and reeler mutant mice, which are characterized by profuse architectonic anomalies. The adult reeler phenotype is characterized by extreme abnormalities of cell positioning in the telencephalic and cerebellar cortices as well as by distinct architectonic anomalies in non-cortical structures such as the inferior olive, the facial nerve nucleus and other brainstem nuclei. Studies of the embryonic development of these structures reveal that neurons are generated at the normal time and migrate along normal pathways. Moreover, the processes of directional axonal growth, differentiation of class-specific features of neurons and glia, and synaptogenesis appear unaffected by the reeler mutation. In all instances, however, the early cell patterns formed by reeler neurons is consistently less regular than in normal embryos. These data indicate that brain architectonics does not exclusively result from the maturation of cells, neurites and connections, but is also contingent upon a specific stabilization of early neurons at the end of migration. One may infer that the presence of a normal allele at the reeler locus is necessary for this stabilization to occur normally, or that it is submitted to genetic control. Although the factor(s) responsible for the stable configuration of neural cell patterns are still unknown, several hypotheses can be considered. There is ample evidence against the role of diffusible factors, mesodermal components and afferent fiber systems. So far, most data point to the importance of cell-cell interactions which can be of three types: homophilic (neuronal-neuronal), heterophilic (neuronal-glial), or both. The cell-interaction mechanism could have been acquired during brain evolution of the mammalian lineage and the reeler gene could act by perturbing, directly or indirectly, these cell interactions. A better definition of the mechanisms responsible for the organization of nerve cell patterns is central to our understanding of brain development in normal as well as in pathological states. By following the example of recent successful research on invertebrate brain development, we believe that the genetic approach to this important question is a valuable one.