This proposal requests continuation of support for a combined neurochemical and histochemical study of the genetic regulation and development of the dopamine-containing neurons in the brain. The work is focused on a mutant allele that discriminates in its action among the brain's dopaminergic neurons with a striking regional specificity. The genetic mutation to be examined is weaver, an autosomal recessive mutation in mouse in which striatal and nonstriatal targets of the mesotelencephalic dopamine-containing systems are affected or not in a pattern with strict boundaries reproducible in homozygous weaver animals. The pattern strongly suggests separable control of mesolimbic and nigrostriatal systems. Our developmental studies show that this control is exerted during early postnatal life. The gene exerts its effects within a limited developmental period, shows gene dose- dependence and regional specificity. These features are in common with the defect that this gene exerts on a seemingly unrelated population of cells, the cerebellar granule cells.
The aims of the proposal are focused on the role of the dopamine- containing innervation in the development of the striatum, the features that distinguish spared and affected populations of dopamine-containing cells in the weaver mutant, how the genetic control of these subsets of dopamine neurons is regulated, and the definition of features in common between the action of the weaver gene in the cerebellum and in the dopamine system. These studies will require biochemical measurements of and anatomical distribution of tyrosine hydroxylase, dopamine, and tyrosine hydroxylase messenger RNA in addition to the anatomical distribution of substance P, somatostatin, enkephalin. Synaptosomal uptake of 3H dopamine and retrograde tracer studies will be used to examine axonal growth and maintenance. 3H thymidine mapping and the use of chimeric mice and examination of glial cells will aid the developmental studies. We intend to identify the primary and secondary targets of the weaver gene in the midbrain and/or striatum through the use of mouse chimeras that are mixtures of genetically normal and genetically weaver cells. This work has the eventual goal of uncovering the orderly sequence of genetic information which governs the development of dopamine-containing neurons. The disease produced by the weaver gene bears so much resemblance to two diseases of the basal ganglia, Parkinson's disease and Huntington's disease, in terms of the topography of cell and/or axonal loss in the basal ganglia, that we are encouraged to search for common principals underlying these disease states.
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