To move toward a molecular genetic understanding of mammalian brain development, we have undertaken a comprehensive study of the molecular genetics of mouse cerebellum development. First, we are investigating the role of somatostatin in cerebellum development by introducing a knockout mutation of this gene into mice using embryonic stem cells. Both somatostatin and specific receptors are transiently expressed in the developing cerebellum, in addition to other brain regions, suggesting a developmental role for somatostatin in addition to its adult functions. Chimeric mice carrying this mutation have been produced, and are being assayed for germline integration. Analysis of homozygous somatostatin disruption mutants will reveal the role of transient somatostatin expression in the developing cerebellum. Second, we previously identified 6 novel genes whose expression is regulated during cerebellum development. All are down regulated in the adult. In situ hybridization analysis of developing brain sections has shown that one of these genes is specifically expressed in granule cells of the external germinal layer and during migration through the molecular and Purkinje layers, but is down regulated in cells upon reaching their final position in the internal granule cell layer. After the complete sequence of this gene is obtained, it will be a candidate for a knockout mouse. Third, we are isolating genes defined by mutations affecting discrete aspects of cerebellum development. We have isolated human genomic clones covering 1.0 Mb of the most likely region of 2 Xb surrounding the weaver locus. From this region we have screened 0.5 Mb for transcribed sequences and identified two novel genes expressed in the developing cerebellum; these are being worked up as candidates for the weaver gene which specifically affects the morphogenesis and migration of the post mitotic granule cells.