Sequence of developmental abnormalities leading to granule cell deficit in cerebellar cortex of weaver mutant mice

Abstract

Golgi, electronmicroscopic and autoradiographic analyses of the developing cerebellar cortex were carried out in homozygous wild‐type (+/+), heterozygous (+/wv), and homozygous weaver (wv/wv) littermates. At 3 to 15 days after birth, when granule cells normally migrate from the external granular layer inward to their adult position, the somas of postmitotic granule cells in +/+ animals move along straight elongated Bergmann glial fibers which span the molecular layer. As early as postnatal day 3 and increasingly for about the next ten days, some Bergmann fibers in the +/wv cerebellum are enlarged, irregular in caliber, electronlucent and may contain dense bodies and vacuoles. Some granule cells contiguous with the altered Bergmann fibers have round rather than elongated somas, while some have lost contact with Bergmann fibers and appear to degenerate several days after their genesis. Most other granule cells migrate slowly but do eventually reach the granular layer, so that the pathology is less striking in adult than in developing heterozygotes. In wv/wv cerebella, radially‐aligned Bergmann fibers appear reduced in number during the developmental period, and few of them display normal cytological features. Few normally migrating granule cells were observed. Most granule cells fail to form axons and die in the external granular layer close to their site of genesis. While the primary genetic defect is unknown, the Bergmann glial disorder appears to precede the migration failure of granule cells and this in turn, along with impaired axon genesis, appears to be a factor leading to granule cell death.