Role of development signaling pathways in testicular physiology and spermatogenesis

发育信号通路在睾丸生理学和精子发生中的作用

• 批准号: RGPIN-2017-03745
• 负责人: Boerboom, Derek
• 金额: $ 2.04万
• 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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682757
• 关键词: Role; development; signaling; pathways; testicular

Testosterone, the male reproductive hormone, is necessary for normal development, the initiation of puberty and sperm cell production in the testes in all mammalian species. Inadequate testosterone production has a range of negative consequences, such as undescended testes, pseudohermaphroditism and infertility. Although it has long been known that testosterone production by the testicular Leydig cells is stimulated by pituitary luteinizing hormone (LH), our understanding of how this regulatory process works at a molecular level remains very rudimentary. Our group has uncovered strong preliminary evidence to suggest that Hippo, an intracellular signaling pathway traditionally associated with embryonic development, is activated following LH binding. Hippo signaling then acts to suppress the activity of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), two signaling molecules that seem to block the transcription of genes involved in testosterone synthesis. In the present proposal, we will confirm our preliminary findings and identify the key players within the Hippo pathway that act downstream of LH. The effects of YAP and TAZ on the activity of steroidogenic genes will be studied in detail. Finally, we will create transgenic mice in which critical Hippo pathway genes will be deleted in their Leydig cells, and we will study the consequences of their deletion on testosterone production, steroidogenic gene expression, spermatogenesis and fertility. Taken together, these studies should unearth previously unsuspected mechanisms of regulation of testosterone synthesis, and may provide insight into both the etiology and potential therapies for testosterone insufficiency.

睾酮是一种雄性生殖激素，对所有哺乳动物的正常发育、青春期的开始和睾丸中精子细胞的产生都是必需的。睾酮分泌不足会产生一系列负面后果，如睾丸隐睾、假雌雄同体和不育。虽然人们早就知道睾丸间质细胞的睾酮分泌是由垂体黄体生成素（LH）刺激的，但我们对这种调节过程在分子水平上是如何起作用的理解仍然非常初级。我们的研究小组已经发现了强有力的初步证据，表明传统上与胚胎发育相关的细胞内信号通路Hippo在LH结合后被激活。Hippo信号随后抑制yes相关蛋白（YAP）和带pdz结合基序的转录共激活因子（TAZ）的活性，这两种信号分子似乎阻断了参与睾酮合成的基因的转录。在目前的提案中，我们将确认我们的初步发现，并确定Hippo通路中作用于LH下游的关键参与者。本文将详细研究YAP和TAZ对甾体生成基因活性的影响。最后，我们将创建转基因小鼠，在其间质细胞中删除关键的Hippo通路基因，我们将研究这些基因的删除对睾酮产生、类固醇基因表达、精子发生和生育的影响。综上所述，这些研究应该揭示了以前未被怀疑的睾酮合成调节机制，并可能为睾酮不足的病因和潜在治疗提供见解。