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

Hippo 信号在睾丸中的作用、作用机制和调节

• 批准号: RGPIN-2020-05230
• 负责人: Boyer, Alexandre
• 金额: $ 2.4万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740466
• 关键词: Roles; mechanisms; action; regulation; Hippo

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.

支持细胞在睾丸中占有独特的地位，在其发育以及青春期后精子发生的建立和维持中起着重要作用。支持细胞启动和协调性别决定的过程，它们的数量决定每天精子的生产能力，它们形成一个免疫保护环境，保护生殖细胞，并为它们提供结构和营养支持。尽管这些作用的重要性，调节这些生理功能的信号通路仍然不完全清楚。Hippo是一种进化上保守的信号通路，通过抑制Yes相关蛋白（雅普）和具有PDZ结合基序的转录共激活因子（TAZ）的活性来调节器官大小和细胞命运决定、分化和增殖。然而，关于海马信号在睾丸中的作用知之甚少。我们最近的工作表明，雅普和Taz的缺失降低了未成熟支持细胞中雄性性别决定基因的表达，增加了雌性性别决定基因的表达，而我们对转基因小鼠模型的初步分析表明，在该模型中，大肿瘤抑制因子同源物激酶1和-2（Lats 1和Lats 2，两种主要的Hippo信号激酶）在未成熟的支持细胞中失活，表明它们的丢失导致睾丸发育不良。在本提案中，我们将扩展这些数据。我们将首先确定LATS 1和LATS 2在发育和成熟支持细胞中的生理功能和作用机制。我们将通过详细研究上述转基因小鼠模型和创建一个新的转基因小鼠模型，其中这些激酶在成熟的支持细胞中失活，以确定精子发生是如何受到这种损失的影响。此外，我们将确定支持细胞形成的微环境如何保护和支持GEM细胞本身调节Hippo信号的激活。最后，我们将确定Hippo信号如何有助于性别决定调节。总之，这些研究将揭示完全新的机制调节支持细胞的增殖，成熟和生理功能。我们的研究结果将有助于了解整个哺乳动物的精子发生和不育，并将构成一个宝贵的补充，我们目前的知识男性生殖。