Sox Transcription Factors: Transcriptional Regulation of Mediators of Testicular Cell-to-Cell Interactions

Sox 转录因子：睾丸细胞间相互作用介质的转录调节

• 批准号: RGPIN-2018-05219
• 负责人: Martin, Luc
• 金额: $ 2.62万
• 依托单位: Université de Moncton
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=745023
• 关键词: Sox; Transcription; Factors; Transcriptional; Regulation

Members of the Sox family of transcription factors are well conserved among vertebrate species and belong to the great high-mobility group (HMG) family. Sox members are involved in regulation of various stages of fetal development and, consequently, are expressed in numerous tissues. To ensure their specificity of action, they rely on recruitment of certain partners and on post-translational modifications. In vertebrates, more than 20 members of the Sox family have been characterized, of which several are expressed in the testis. Two members, Sry and Sox9, play important roles in sex determination and differentiation in mammals. However, the Sry gene is only expressed during a limited but critical time frame during early development. During later phases of male gonadal development such as onset of puberty, Sox-dependent regulation of transcription involves other members of the Sox family. Interestingly, putative regulatory elements for Sox transcription factors are located in the promoter regions of several genes related to cell-to-cell interactions in mammals, including genes encoding connexins and cadherins. Moreover, Sox members can interact with AP-1 family members, also known to regulate transcription of these genes. Thus, Sox and AP-1 transcription factors may cooperate to regulate transcription of genes important for cell-to-cell interactions between Leydig cells and/or between Sertoli cells, leading to appropriate testosterone production and maintenance of spermatogenesis. The objectives of this proposal are to better define the regulatory mechanisms of Sox family members in the regulation of Cx43 expression, determine how Sox members regulate the expressions of genes encoding cadherins, define the role of Pcdhgc3 expression in Leydig cells function and how Sox members are involved in its regulation, and characterize the mechanisms regulating the expression of Sox9 within adult Sertoli cells. The current proposal is novel in that transcriptional regulation of components of cell-to-cell interactions specific to testicular cells is not entirely elucidated and is critical for appropriate fertility. So far, no regulatory elements for Sox members have been confirmed in promoters of genes encoding connexins or cadherins, even though some of these have been upregulated by these factors. The proposed research will have a great significance in our understanding of basic principles responsible for Sox mechanisms of gene regulation leading to changes in cell-to-cell interactions within the testis. Previous work on the role of Sox members in gonadal function have focused on sex determination and differentiation during fetal development. Therefore, elucidating the role and mechanisms of action of members of the Sox family in regulation of gonadal function from onset of puberty to adulthood will constitute an invaluable addition to our current knowledge.

Sox转录因子家族的成员在脊椎动物物种中是非常保守的，并且属于大高迁移率族（HMG）家族。Sox成员参与调节胎儿发育的各个阶段，因此在许多组织中表达。为了确保其作用的特异性，它们依赖于某些合作伙伴的招募和翻译后修饰。在脊椎动物中，Sox家族的20多个成员已被鉴定，其中几个在睾丸中表达。Sry和Sox 9在哺乳动物的性别决定和分化中起着重要作用。然而，Sry基因仅在早期发育期间有限但关键的时间范围内表达。在雄性性腺发育的后期阶段，如青春期的开始，Sox依赖的转录调节涉及Sox家族的其他成员。有趣的是，Sox转录因子的假定调控元件位于哺乳动物中与细胞间相互作用相关的几个基因的启动子区，包括编码连接蛋白和钙粘蛋白的基因。此外，Sox成员可以与AP-1家族成员相互作用，AP-1家族成员也已知调节这些基因的转录。因此，Sox和AP-1转录因子可能合作调节基因的转录，这些基因对Leydig细胞和/或Sertoli细胞之间的细胞间相互作用很重要，从而导致适当的睾酮产生和维持精子发生。本提案的目的是更好地定义的调控机制的Sox家族成员在调节Cx43的表达，确定Sox成员如何调节基因编码的钙粘蛋白的表达，定义的作用Pcdhgc 3的表达在Leydig细胞的功能和Sox成员是如何参与其调节，并表征的机制，调节成人支持细胞内的Sox 9的表达。目前的建议是新颖的，因为睾丸细胞特异性的细胞间相互作用的转录调控成分尚未完全阐明，并且对于适当的生育力至关重要。到目前为止，没有调控元件的Sox成员已被证实在启动子的基因编码连接蛋白或钙粘蛋白，即使这些已经上调这些因素。这项研究将对我们理解Sox基因调控机制的基本原理具有重要意义，该机制导致睾丸内细胞间相互作用的变化。以前的工作中的作用，Sox成员在性腺功能集中在性别决定和胎儿发育过程中的分化。因此，阐明的作用和作用机制的成员的Sox家族在调节性腺功能从青春期开始到成年将构成一个宝贵的除了我们目前的知识。