Role of developmental signaling pathways in testicular physiology and spermatogenesis

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Spermatogenesis, the process by which mature sperm cells are produced in the testis, is one of the most complex processes that occur in the body and is essential for sexual reproduction. Spermatogenesis consists of a carefully orchestrated series of events beginning with the division of spermatogonial stem cells (SSCs), the adult stem cell population that sits atop the male germ cell developmental hierarchy. SSC division results in the regeneration of the SSC and/or the production of Apr spermatogonia that are destined to differentiate into sperm cells. Our current knowledge of the molecular mechanisms that regulate the decision by SSCs to divide or to differentiate into spermatogonia is very limited. However, our group and others have recently discovered that the WNT family of signaling molecules may play important roles. For instance, WNT5a secreted by Sertoli cells appears critical for SSC self-renewal, and acts via activation of non-canonical signaling pathways in SSCs. Conversely, the activation of another WNT signaling cascade known as the canonical pathway has been associated with spermatogonial differentiation. In light of these findings, we propose 1) to identify the physiological receptor for WNT5a in SSCs; 2) to study the effects of disrupting or increasing canonical WNT signaling in SSCs in vitro and in vivo; and 3) to identify the downstream transcriptional targets of the canonical and non-canonical WNT signaling pathways in SSCs. Taken together, these studies should unearth previously unsuspected mechanisms of regulation of some very fundamental aspects of testicular physiology, and will further our understanding of male fertility and of stem cell biology.