DEFECTS OF NEURONAL MIGRATION AND THE PATHOGENESIS OF CORTICAL MALFORMATIONS ARE ASSOCIATED WITH SMALL EYE (SEY) IN THE MOUSE, A POINT MUTATION AT THE PAX-6-LOCUS

The mouse Small eye (Sey) locus is situated on chromosome 2. Molecular analyses have shown that Sey(Neu) represents a point mutation leading to a splice site error and loss of the functional gene product. The S ey locus has been shown to be identical with the paired box (Pax)-6 ge ne, which contains paired-like and homeobox domains and is a developme ntal control gene. Pax-6 expression occurs in many parts of the centra l nervous system during embryogenesis. Therefore, we may expect the Se y mutation to result in abnormal development of the central nervous sy stem. The present study shows that Pax-6 mutation has a bimodal effect upon neurogenesis in mouse: it causes a delay of premigratory neurons in a stage-, region-, and gene-dose-dependent manner. Additionally, S ey mutation impairs axonal growth and differentiation. Neurons of the cortical plate cease differentiation on approximately day 16 of gestat ion and appear to have increased cohesion: their cytoplasm is swollen and vacuolated. These changes coincide both with reduced formation of axons and with the onset of vacuolar degeneration in existing axons, g lial cells and radial glial fibers. Consequently, there is an impairme nt of the peripheral migration of putative neurons so that the neonata l lesion pattern of the neocortical roof becomes dominated by a broad spectrum of neuronal migration disorders.