Using a simple neuromuscular system, this proposal focuses on the influence of androgens on the cellular mechanisms operating during normal development which produce sex differences in neuron number, morphology, and connectivity. The experiments proposed examine the development of two sexually dimorphic nuclei in the rat spinal cord, the spinal nucleus of the bulbocavernosus (SNB) and the dorsolateral nucleus (DLN). These nuclei innervate muscles of the perineum, and both the nuclei and the muscles they innervate are present in males but reduced or absent in females. It has been established that the sex difference in the SNB is produced by an androgen-regulated cell death, as well as a possible androgen enhancement of SNB migration from the DLN. Because SNB development is related to the DLN, how the DLN's dimorphic motoneuron number and efferent projections develop will be examined to test the influence of androgens on promoting axon outgrowth and cell survival. Secondly, several experiments will address whether androgens act directly or indirectly to promote motoneuron survival, and will further define whether androgens act alone or in combination with their estrogenic metabolites to masculinize the SNB/DLN system. Finally, SNB and DLN development will be examined in females treated prenatally with dihydrotestosterone propionate (DHTP). These females paradoxically lack SNB motoneurons but retain their perineal musculature, which is now innervated by motoneurons anomalously located in the DLN. Determining whether DHTP actively inhibits the development of the SNB or merely passively fails to promote its survival will yield information on the factors which normally control cell migration, death, and specification, as well as further clarifying the influence of androgens on these processes during development. A better understanding of the cellular mechanisms of sexual differentiation holds great promise for the treatment/prevention of abnormalities of sexual differentiation in humans.
