Role of developmental signaling pathways in testicular physiology and spermatogenesis

精子发生是睾丸中产生成熟精子的过程，是体内发生的最复杂的过程之一，对有性生殖至关重要。 精子发生由精原干细胞（SSC）分裂开始的一系列精心策划的事件组成，精原干细胞是位于男性生殖细胞发育层次之上的成体干细胞群。 SSC分裂导致SSC的再生和/或注定分化成精子细胞的Apr精原细胞的产生。 我们目前对精原干细胞分裂或分化为精原细胞的分子机制的认识非常有限。 然而，我们的团队和其他人最近发现，信号分子的WNT家族可能发挥重要作用。例如，由支持细胞分泌的WNT 5a似乎对SSC自我更新至关重要，并且通过激活SSC中的非经典信号传导途径起作用。 相反，另一个被称为经典途径的WNT信号级联的激活与精原细胞分化有关。 鉴于这些发现，我们提出1）鉴定SSCs中WNT 5a的生理受体; 2）研究在体外和体内破坏或增加SSCs中经典WNT信号传导的作用;以及3）鉴定SSCs中经典和非经典WNT信号传导途径的下游转录靶点。 总之，这些研究应该揭示以前未被怀疑的睾丸生理学的一些非常基本的方面的调节机制，并将进一步加深我们对男性生育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.