Role of development 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。精子发生包括一系列精心安排的事件，从精原细胞（生殖细胞干细胞群）的不对称分裂开始，随后减数分裂产生单倍体精子，最后精子分化为成熟精子，后一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器，这些雄激素是由睾丸间质细胞在睾丸内局部产生的。睾丸间质细胞远不是一个静态的群体，而是从睾丸间质间质前体细胞中产生并不断更新。因此，精子发生和间质细胞的功能都依赖于两种不同的干细胞/祖细胞群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这两种细胞类型中发挥重要作用，作为间质细胞增殖和精子发生的调节剂。鉴于此，我们建议1)鉴定睾丸中介导Wnt信号的特定Wnt通路组分；2)在体内研究以细胞特异性方式干扰或增加睾丸Wnt信号的影响；3)鉴定间质细胞中Wnt信号的下游转录靶点。综上所述，这些研究将揭示睾丸生理学一些非常基本方面的调控机制，并将进一步加深我们对男性生育能力和干细胞/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.