Role of developmental signaling pathways in testicular physiology and spermatogenesis

精子发生是睾丸中成熟精子细胞产生的过程，是人体中最复杂的过程之一，对有性生殖至关重要。精子发生由一系列精心安排的事件组成，从精原干细胞（SSCs）的分裂开始，SSCs是位于男性生殖细胞发育层次顶端的成体干细胞群。SSC分裂导致SSC的再生和/或产生Apr精原细胞，这些精原细胞注定要分化成精子细胞。我们目前对调节ssc分裂或分化为精原细胞的分子机制的知识非常有限。然而，我们的团队和其他人最近发现信号分子WNT家族可能发挥重要作用。例如，Sertoli细胞分泌的WNT5a似乎对SSC自我更新至关重要，并通过激活SSC中的非规范信号通路起作用。相反，另一种WNT信号级联的激活被称为规范通路，与精原细胞分化有关。鉴于这些发现，我们建议1)在ssc中鉴定WNT5a的生理受体；2)在体外和体内研究破坏或增加SSCs中典型WNT信号的影响；3)鉴定ssc中典型和非典型WNT信号通路的下游转录靶点。综上所述，这些研究应该揭示了睾丸生理学一些非常基本方面的以前未被怀疑的调节机制，并将进一步我们对男性生育能力和干细胞生物学的理解。

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.