This study focuses on mutations affecting the nervous system in mice and is designed to increase our understanding of how genes control the development, organization, and maintenance of this extraordinary organ. We plan to construct interspecies chimeras by fusing 8-cell embryos of two species, Mus musculus (the house mouse) and Mus caroli. The cells of each species will be detected in autoradiograms with a radioactive synthesized DNA fragment that binds selectively to satellite DNA of one or the other species, but not both, the method will allow tracing of the clonal history and sorting out of developing nervous system cells. We will also seek to define specific genetic loci that modify either the severity or the apparent dominance-recessive relationships of a disease-causing mutation. The test case is a mouse mutation named Purkinje cell degeneration, pcd, a recessive which causes cerebellar ataxia and progressive visual loss; severity of the disease is increased by another recessive locus linked to pcd on chromosome 13, and it is converted to dominant expression by another locus on chromosome 7 and probably an additional locus; this model may explain some of the puzzles in human inherited disease pedigrees. We will also explore the relationships among various neurons and their target cells in the developing and mature cerebellum, with computer graphics methods for automated 3-D reconstruction of cells, specific ligand autoradiography, and mutant analysis. Finally, we propose to develop critical inbred stocks that will allow quantitative comparisons between mutants, and we will give the first description of a number of new mouse inherited neurological diseases.
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