This project will use recombinant DNA probes for individual species of mRNA to study morphogenesis and cytodifferentiation in the developing mouse cerebellum. By examining the cellular distribution and the temporal pattern of individual gene expression in normal and mutant mice, we will evaluate four hypotheses: (1) The five types of neuron of the mature cerebellum express sets of genes that only partially overlap, both during cytodifferentiation and in the fully differentiated state; (2) individual neuron types are most likely to differ in the particular species of messenger RNAs that accumulate to high or moderate concentrations; (3) genes for glutamic acid decarboxylase are expressed at different times in four of the five neuron types; and (4) neuroblasts in the two germinal layers that give rise to the five cerebellar neuron types do not begin to express cell type specific genes until they start their characteristic migrations into new microenvironments. The preparation of probes for mRNAs preferentially expressed in individual neuron types will also allow the examination of a further hypothesis concerning hereditary ataxias both in mice and humans - that the molecular lesions in these conditions are located in genes that are preferentially expressed in the affected cell types. This hypothesis will be tested for four cerebellar mouse mutants whose primary defects appear to be in Purkinje cell development. We will also search for changes in the structure of cerebellum-specific genes in humans with hereditary ataxias. This project will provide basic information about the expression of specific genes during the development of a region of the brain that has been extremely well studied from morphological, physiological and genetic perspectives. If the proposed hypotheses about the molecular lesions in murine and human hereditary ataxias are correct, this work will also lead to a direct approach to diagnosis, and future therapies, for human neurogenetic disorders.
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