<br/><br/>Wolffian/Epididymal duct Morphogenesis.<br/> The formation of tubes is a fundamental biological process during the genesis of many organs, for example, kidney, intestine, brain, heart, and lungs. In fact, very few organs do not form tubular structures at some point in their development. Formation of the tubular structure is then followed by unique morphogenic events in each organ to generate their final adult structure. The morphogenesis of the Wolffian/epididymal duct is unusual in that it exhibits a unique pattern in that it forms a simple tube and then systematically elongates and coils dramatically. Surprisingly, the fully developed epididymis is 1.2 meters long in the mouse, 3 meters long in the rat and a remarkable 6 meters long in the human. The goal of this laboratory is to understand the mechanisms by which this important biological tube elongates and coils because without a fully developed and functional epididymis, male infertility will result. We are especially interested in the contribution of cell proliferation and cell rearrangements towards duct elongation. Data obtained from using mice that are null for protein tyrosine kinase 7 supports the hypothesis that cell rearrangements are under the regulation of the planar cell polarity/non-canonical Wnt pathway. It appears that signal transduction pathways involving MAPK, PTEN and Src regulate cell proliferation.<br/><br/>Regulation of epididymal initial segment function.<br/>The initial segment region of the epididymis has been clearly shown to play a major role in male fertility because without an initial segment, infertility results. Therefore, we are very much interested in the mechanisms by which this important region of the epididymis is regulated. Androgens clearly play a role in the regulation of epididymal function but we, and others, have shown that testicular luminal fluid factors, lumicrine factors, play a major role also. We have identified a number of growth factors as candidate lumicrine factors that regulate cell proliferation and survival of the initial segment. We are currently identifying the downstream signaling pathways and genes that are regulated by lumicrine factors. C-ros, an orphan tyrosine kinase receptor in highly expressed in the initial segment and C-ros null male mice are infertile. Therefore, we are examining the manner by which this important gene plays a role in male fertility and also examining this gene as a potential target for the development of a male contraceptive.