Androgens exert trophic effects on muscle and motor neurons through activation of the androgen receptor (AR). At the cellular level, androgens increase translational activity of polyribosomes, increase transport of nutrients across the membrane, and increase mitochondrial DNA synthesis. At the organismal level, AR activation leads to masculine differentiation of both genital and extra-genital tissues, including motor neurons and muscle. These effects are thought to arise from control of gene expression by AR. Much of what is known of AR function has been deduced from phenotypic effects of AR mutations. Mutations causing complete loss of AR function in XY individuals result in a female phenotype, with diminution of skeletal muscle mass appropriate to female somatic differentiation. A trinucleotide (CAG) repeat expansion in the AR gene causes spinal and bulbar muscular atrophy (SBMA), a motor neuron degenerative disorder. The SBMA mutation resembles CAG repeat mutations seen in Huntington's disease and several other neurodegenerative conditions, suggesting that these CAG repeat diseases develop in similar ways. To understand the connection between the CAG repeat expansion and motor neuron degeneration in SBMA, and to develop effective therapy, we need useful models of the disease process. Such model systems could also help us to understand the normal function of AR in the nervous system, and could provide clues to the pathogenesis of other neurodegenerative disorders caused by CAG repeat expansions. My approach uses transgenic technology to establish mouse lines carrying either the AR mutation of SBMA or a normal AR construct. I have established 3 transgenic mouse lines with inducible expression of human AR. Preliminary evidence indicates that the AR transgene can correct a spontaneous mouse AR mutation causing complete androgen insensitivity (tfm). I plan to take advantage of this effect to investigate a fundamental question in human development: how does AR determine neuromuscular sexual dimorphism? Quantitative neuropathologic assessment will be done on mouse lines carrying either the abnormal or normal AR transgene. I will study the effect of AR on differentiation of skeletal muscle in transgenic tfm animals lacking endogenous AR. Finally, the biological activities of SBMA vs. normal AR will be compared in terms of their capacity to increase activity of an androgen-regulated enzyme, ornithine decarboxylase. These transgenic lines thus offer an opportunity to investigate the importance of AR in neuromuscular sexual dimorphism concurrently with studies aimed to elucidate the mechanism of motor neuron degeneration in SBMA.
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