The aim of this research is an understanding of the cellular and molecular mechanisms that govern the sexual differentiation of the brain. In particular, we are investigating how male-specific patterns of secretion of gonadal androgens regulate the proliferation, survival, synaptic connectivity and function of target muscle and motor neurons. We have exploited a highly sexually dimorphic system--the neurons and muscles that control vocalizations in X. laevis--to identify key events in the development of functional sex differences.
Our specific aims now are to further understand how androgen secretion controls sexual differentiation at the cellular level and how a set of molecules--the androgen receptor, gap junction proteins, myosin isoforms-- participate in this ontogenetic process. We will examine the development of sexually dimorphic muscle fiber types in larynx using histochemistry and immunocytochemistry. Myosin isoforms will be separated biochemically; we will determine when sex typical expression first diverges. We will investigate the molecular basis and ontogenetic history of dye coupling of muscle fibers in adult females. We plan to examine sex differences in acetylcholine release and number of synaptic terminals at the laryngeal neuromuscular junction. The origins of sex differences in laryngeal motor neuron number and sexually dimorphic CNS connectivity will be explored. We will measure androgen levels and receptor expression in brain just after the gonads differentiate. Using endocrine application and ablation, the critical periods for hormone action on key cellular and molecular processes will be established. The relative contributions of direct action on muscle and nerve targets versus indirect, synaptically mediated, actions will be assessed. Androgen secretion during development controls brain sexual differentiation in most vertebrates. Disorders in endocrine function or in androgen receptor proteins are associated with clinical dysfunction including pseudohermaphroditism, testicular feminization, neuroendocrine abnormalities and alterations in gender identity. An understanding of basic processes affected by steroid hormones in nerve and muscle can be derived from study in animal models and will provide useful insights into underlying cellular and molecular mechanisms of human disorders.
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