Grant: Discovery Grants Program - Individual

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.