This long-term grant has contributed many of the primary analyses of disease phenotypes in mice with inherited neurological diseases, and thus has provided model systems for the analysis of developmental cell interactions in the complex nervous system of mammals. It has also provided core material for experimental study of disease mechanisms relevant to our understanding of human degenerative diseases of the nervous system. The mouse, for technical reasons, is by far the most relevant animal species for the many types of genetic studies that are now at the center of biomedical science. A primary research aim for the forthcoming five-year cycle involves the continuation of our studies on cell interactions in development. We will turn to the early embryo to test the hypothesis that the first incoming axonal systems influence the deployment of the early-forming neuronal populations that are migrating into the developing cerebellar cortex. We propose that also in the first weeks after birth, when mice arc still very immature, a similar set of interactions in time and space between incoming axons and at least two major neuronal populations mediate the acquisition of adult cerebellar organization. The data relevant to test these ideas will come from new methods for examining quantitatively and efficiently the numbers, and the three dimensional positions and configurations, of cellular elements in whole mounts and thick slices of tissue examined by confocal microscopy. We will use as our experimental material a large series of available mouse mutations that perturb the development or viability of neurons and allow us to explore developmental mechanisms in the relatively inaccessible immature mammalian cerebellum. Further, we will seek a specific mechanism in the nr mutant, where we hypothesize that cerebellar granule cells may mediate the death of related Purkinje neurons through a toxic action of excitatory neurotransmitter molecules. We will also seek new insights into late-life neurodegenerative diseases by examining cell relationships in several mutants where Purkinje neurons die relatively early in life, and then presynaptic granule cell neurons die secondarily at much later ages.
A final aim i s to continue the description of new inherited mouse disorders, and to develop, characterize, and distribute the specialized genetic stocks necessary to make full use of the potential of the science of genetics for increasing our understanding of the formation, organization, and diseases of the nervous system.
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