Roles, mechanisms of action and regulation of Hippo signaling in the testis

点击翻译按钮获取中文摘要

Sertoli cells occupy a unique place in the testes, playing major roles in their development and in the establishment and maintenance of spermatogenesis after puberty. Sertoli cells initiate and coordinate the process of sex determination, their numbers determine daily sperm production capacity, and they form an immunoprotective environment that protects germ cells and offers them structural and nutritional support. Despite the importance of these roles, the signaling pathways that regulate these physiological functions remain incompletely understood. Hippo is an evolutionarily conserved signaling pathway that regulates organ size and cell fate determination, differentiation and proliferation by suppressing the activity of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). However, very little is known about the role of Hippo signaling in the testis. Our recent work showed that the loss of Yap and Taz decreases the expression of male sex-determining genes and increases the expression of female sex-determining genes in immature Sertoli cells, while our preliminary analysis of a transgenic mouse model in which the large tumor suppressor homolog kinases 1 and -2 (Lats1 and Lats2, the two main Hippo signaling kinases) are inactivated in immature Sertoli cells shows that their loss leads to testicular dysgenesis. In the present proposal, we will expand upon these data. We will first identify the physiological functions and mechanisms of action of LATS1 and LATS2 in developing and mature Sertoli cells. We will determine how spermatogenesis is impacted by this loss by studying in detail the aforementioned transgenic mouse model and by creating a new transgenic mouse model in which these kinases are inactivated in mature Sertoli cells. Furthermore, we will determine how the microenvironment formed by the Sertoli cells to protect and support gem cells itself regulates the activation of Hippo signaling. Finally, we will determine how Hippo signaling contributes to sex determination regulation. Taken together, these studies will unearth completely novel mechanisms regulating the proliferation, maturation and physiological functions of Sertoli cells. Our findings will contribute to understanding spermatogenesis and infertility across the mammalian spectrum and will constitute an invaluable addition to our current knowledge of male reproduction.