Sox transcription factors: Regulatory mechanisms and impact on steroidogenesis

已知Sox家族的转录因子Sry和Sox 9在哺乳动物的性别决定和分化中发挥重要作用。该家族的20多个成员已被鉴定，其中几个在睾丸中表达。为了确保其作用的特异性，Sox蛋白依赖于配偶体的募集和翻译后修饰。然而，它们在类固醇合成的转录调控中的作用从未被研究过。有趣的是，假定的结合位点的Sox成员存在于几个类固醇基因的启动子。因此，Sox家族成员可能在Leydig细胞类固醇合成的转录调控中起着至关重要的作用。这些细胞提供睾丸激素，对维持男性生育力和避免与衰老相关的男性更年期相关症状非常重要。类固醇生成可以在不同水平调节，如性腺（用于类固醇生成基因）、垂体（通过调节LH和FSH产生）和下丘脑（通过调节GnRH产生）。因此，我的研究计划的主要目标是确定的作用，Sox成员的功能调节下丘脑-垂体-性腺轴，重要的性类固醇的生产。目前的提案旨在确定哪些Sox成员在啮齿动物雄性性腺中表达，它们调节哪些基因以及哪些机制调节它们的活动。总之，不同的分子和细胞生物学方法将被用来更好地了解Sox转录因子在Leydig细胞功能中的作用。与其他组织一样，Sox成员在类固醇生成细胞中可能是功能冗余的，这解释了Sox缺陷小鼠模型中类固醇生成表型的缺乏。本研究结果对脊椎动物性腺类固醇合成的基础生理学和内分泌学研究具有重要意义，并可能与新型男性避孕方法有关。此外，我们的研究结果将有助于更好地了解前列腺癌的发展和进展。

Members of the Sox family of transcription factors, Sry and Sox9, are known to play important roles in sex determination and differentiation in mammals. More than 20 members of this family have been characterized, of which several are expressed in the testis. To ensure their specificity of action, Sox proteins rely on recruitment of partners and post-translational modifications. However, their role in transcriptional regulation of steroidogenesis has never been investigated. Interestingly, putative binding sites for Sox members are present in the promoters of several steroidogenic genes. Thus, Sox family members might play a crucial role in transcriptional regulation of steroidogenesis in Leydig cells. These cells supply testosterone important to maintain fertility in male and to avoid andropause related symptoms associated to aging. Steroidogenesis can be regulated at different levels such as gonads (for steroidogenic genes), pituitary (by regulating LH and FSH productions) and hypothalamus (by regulating GnRH production). Therefore, the main goal of my research program is to define the role of Sox members in functional regulation of the Hypothalamic-Pituitary-Gonadal axis, important for sex steroids production. The current proposal aims to identify which Sox members are expressed in rodent male gonads, which genes they regulate and what mechanisms regulate their activities. Overall, different approaches of molecular and cell biology will be used to better understand the role of Sox transcription factors in Leydig cells' function. As in other tissues, Sox members might be functionally redundant in steroidogenic cells, explaining the lack of steroidogenic phenotypes in Sox-deficient mice models. Results from this proposal will have a great significance for basic physiology and endocrinology of gonadal steroidogenesis in vertebrates and might be relevant for novel male contraception. In addition, our results will contribute to a better understanding of prostate cancer development and progression.