Role of development 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。 精子发生包括一系列精心安排的事件，首先是精原细胞（生殖细胞干细胞群）的不对称分裂，然后是减数分裂产生单倍体精子细胞，最后是精子细胞分化为成熟精子，后一个过程通常被称为精子发生。 虽然我们对调节和协调精子发生的分子机制的了解仍然不完整，但已经确定雄激素是关键的效应物，并且这些雄激素在睾丸内由Leydig细胞局部产生。 Leydig细胞不是一个静止的群体，而是从位于睾丸间质的间充质前体细胞类型中产生并不断更新。 因此，精子发生和Leydig细胞功能都依赖于两个不同的干/祖细胞群体的增殖和分化的精确调节。 我们的初步数据，加上最近的一些研究，表明一个名为Wnts的信号分子家族可能在两种细胞类型中发挥重要作用，作为Leydig细胞增殖和精子生成的调节因子。 有鉴于此，我们提出1）鉴定在睾丸中介导Wnt信号传导的特定Wnt通路组分; 2）研究在体内以细胞特异性方式破坏或增加睾丸Wnt信号传导的影响;和3）鉴定Leydig细胞中Wnt信号传导的下游转录靶点。 总的来说，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能力和干/祖细胞生物学的理解。

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 asymmetrical division of spermatogonia (the germ cell stem cell population), followed by meiosis to produce haploid spermatids, and finally the differentiation of the spermatids into mature spermatozoa, the latter process being commonly referred to as spermiogenesis. While our knowledge of the molecular mechanisms that regulate and coordinate spermatogenesis remains incomplete, it is well established that androgens are critical effectors, and these androgens are produced locally within the testis by Leydig cells. Far from being a static population, Leydig cells arise and are continuously renewed from a mesenchymal precursor cell type located in the testis interstitium. Therefore, spermatogenesis and Leydig cell function both depend on the precise regulation of the proliferation and differentiation of two distinct stem/progenitor cell populations. Our preliminary data, coupled to a handful of recent studies, suggest that a family of signaling molecules called Wnts may play major roles in both cell types, functioning as regulators of both Leydig cell proliferation and spermiogenesis. In light of this, we propose 1) to identify the specific Wnt pathway components that mediate Wnt signaling in the testis; 2) to study the effects of disrupting or increasing testicular Wnt signaling in a cell-specific manner in vivo; and 3) to identify the downstream transcriptional targets of Wnt signaling in Leydig cells. 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/progenitor cell biology.