ANDROGEN RECEPTORS IN SPINAL CORD NEURONS--DEVELOPMENT

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This project is intended to characterize the muscle-induced developmental appearance of androgen receptors in embryonic chick spinal cord motoneurons both In Vivo and in culture. The androgen receptor will be characterized with respect to number, binding constant, number classes of sites, and distribution between cytosol and nucleus. The relationship between the appearance of androgen receptors and the muscle factor induced increase in cGMP levels and rate of calcium influx into spinal cord neurons will also be examined. In addition the effects of added androgen, dibutyrl cGMP and varied calcium, on the following neuronal properties will be studied: 1) neuron survival, general growth, neurite extension and cholineacetyltransferase activities. Lastly, the purification and characterization of the inducing muscle factor will be initiated. The project will principally involve biochemical determinations on embryonic tissue and neurons and muscle maintained in tissue culture. The biochemical techniques include: enzymatic assays, radioimmunoassays, radio-ligand binding assays, and ion flux assays. The impetus for this study comes from the hypothesis that motoneuron androgen receptor dysfunction is pathogenic for amyotrophic lateral sclerosis (ALS). The degree to which similar hormonal dysfunction may be pathogenic for other degenerative neuronal diseases, such as Huntington's disease, may be clarified through this study. The long-term objectives of this study involve the following questions: What factors provide for the regulation (up and down) of motoneuron androgen receptors? What role do androgens play in the development and maintenance of internal neuron function and neuron-target interactions? What is the tissue source of the androgens that interact with the motoneuron receptors? And how is the muscle factor that induces the appearance of neuronal androgen receptors developmentally regulated?