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

SOX转录因子家族成员在脊椎动物中保守，属于高迁移率族(HMG)家族。SOX成员参与调节胎儿发育的不同阶段，因此在许多组织中都有表达。为了确保其行动的特殊性，它们依赖于某些合作伙伴的招募和翻译后的修改。在脊椎动物中，已有20多个SOX家族成员被鉴定，其中几个在睾丸中表达。Sry和Sox9两个成员在哺乳动物性别决定和分化中发挥重要作用。然而，Sry基因只在早期发育的有限但关键的时间范围内表达。在男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到SOX家族的其他成员。有趣的是，SOX转录因子的可能调控元件位于哺乳动物细胞间相互作用相关基因的启动子区域，包括编码连接蛋白和钙粘附素的基因。此外，SOX成员可以与AP-1家族成员相互作用，AP-1家族成员也调节这些基因的转录。因此，SOX和AP-1转录因子可能协同调节间质细胞和/或支持细胞之间细胞间相互作用的重要基因的转录，从而导致适当的睾酮产生和精子发生的维持。本研究的目的是为了更好地确定SOX家族成员在调控Cx43表达中的调控机制，确定SOX成员如何调控钙粘附素编码基因的表达，明确Pcdhgc3表达在间质细胞功能中的作用以及SOX成员如何参与其调控，并表征成年Sertoli细胞中Sox9表达的调控机制。目前的建议是新颖的，因为对睾丸细胞特有的细胞间相互作用成分的转录调控并不完全清楚，并且对适当的生育至关重要。到目前为止，在编码连接蛋白或钙粘附素的基因的启动子中还没有证实SOX成员的调控元件，尽管其中一些已经被这些因素上调。这项研究将对我们理解SOX基因调控导致睾丸细胞间相互作用变化的基本原理具有重要意义。以前关于SOX成员在性腺功能中的作用的工作主要集中在胎儿发育过程中的性别决定和分化。因此，阐明SOX家族成员在从青春期开始到成年期的性腺功能调节中的作用和机制将是我们当前知识的宝贵补充。

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.