The overall objective of these studies is to determine how genes instruct the development of the mammalian CNS. The study of mutations that affect nervous system development offers an ideal vantage point to approach this problem. The weaver mutant mouse is the subject of the present proposal, and two aspects of the weaver gene (wv) will be examined: l) The identity of the weaver gene will be sought using the techniques of chromosomal microdissection, cloning, and cDNA screening. This approach takes advantage of the most recent advances in the developmental and chromosomal bases of the weaver mutation. Additionally, the mapping of the weaver locus will be continued using subspecies crosses and DNA markers to identify restriction fragment length polymorphisms closer to the weaver locus and to create tools important for the identification of the wv gene. 2) A cellular developmental section will characterize a target of the wv gene, the cerebellar cell in normal and mutant brains. Experiments will also address the hypothesis that the weaver mutation disrupts the process of axonal outgrowth which then leads to cell death. We will employ the invivo use of axonal markers to image the dynamics of granule cell axonal growth in normal and mutant cerebella. Ultrastructural studies will help characterize genetically normal and weaver granule cells for a broader diagnosis of cell pathology in the etiology of the weaver phenotype of granule cell death. These studies are aimed at obtaining a comprehensive understanding of a single locus, wv: its impact on various cell types, its localization in the mammalian genome, and its contextual relationship to brain development. In particular, the massive neonatal loss of cerebellar granule cells and the progressive loss of substantia nigra dopaminergic neurons that occurs in weaver is pathologically similar to the loss of these neurons in the human conditions of cerebellar hypoplasia and Parkinson's disease.
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