Hormonal Regulation of Sertoli Cell Maturation

描述（由申请人提供）：该项目的长期目标是了解支持细胞在精子发生中的作用。为了实现这一目标，以往的研究主要集中在小鼠Sertoli细胞的基因表达和激素反应以及体细胞与生发细胞的相互作用。这些研究的结果导致了一个中心假设，试图解释支持细胞如何调节精原细胞的成熟和进入精子发生和减数分裂。这一可验证假设的要素包括：A)支持细胞的主要功能作用是调节视黄酸向精原细胞的时空传递。B)维甲酸一旦输送，刺激未分化的精原细胞进入分化途径并最终减数分裂。基因stra8的诱导是这一过程的一个敏感和可靠的标记。C)维甲酸通过支持细胞的传递是一个高度调控的过程，最终导致了精原上皮周期的建立。验证这一假设的实验分为三个特定目的：特定目的1：确定stra8诱导的动力学以及这种诱导在生殖细胞中导致体内和体外分化的程度。具体目标2：确定维甲酸通过支持细胞流向精原细胞是否受到调节，以及如何受到调节，并确定支持细胞的哪些成分是在精原细胞中诱导stra8和启动精原细胞分化的关键。具体目的3：在类视黄醇代谢紊乱的模型中，检查减数分裂的开始和精原上皮周期的建立。该假说认为，卵泡细胞和精原细胞不能接触到循环维甲酸，只有由支持细胞输送的维甲酸才能接触到循环维甲酸。另一个要求是维甲酸输送到卵泡细胞或精原细胞足以推动这些细胞进入分化途径。这一假说提出了一种进入减数分裂的机制，从而预测了精子上皮的周期是如何产生和调节的。本研究项目有可能确定在雄性生殖系中启动精子发生的分子机制，并确定Sertoli细胞在该过程中的作用。这些研究结果可能为解决男性不育和避孕问题提供新的基本方法。

DESCRIPTION (provided by applicant): The long term goal of this project has been to understand the role of Sertoli cells in spermatogenesis. To achieve this goal, previous studies focused on gene expression and hormonal response of murine Sertoli cells and the interactions of the somatic cells with the germinal cells. The results of these studies have led to a central hypothesis that attempts to explain how Sertoli cells regulate the maturation of spermatogonia and the entry into spermatogenesis and meiosis. Elements of this testable hypothesis include: A) A major functional role of the Sertoli cells is to regulate the spatial and temporal delivery of retinoic acid to spermatogonia. B) Once delivered, the retinoic acid stimulates the undifferentiated spermatogonia to enter into a differentiation pathway and ultimately meiosis. Induction of the gene stra8 is a sensitive and reliable marker of this process. C) The delivery of retinoic acid via the Sertoli cells is a highly regulated process and is ultimately responsible for the establishment of the cycle of the seminiferous epithelium. The experiments to test this hypothesis are organized into three specific aims: Specific aim 1: Determine the kinetics of stra8 induction and the extent to which this induction in germ cells leads to differentiation in vivo and in vitro. Specific aim 2: Determine if, and how, the flow of retinoic acid through the Sertoli cells to the spermatogonia is regulated and resolve which components of the Sertoli cells are key for inducing stra8 in spermatogonia and initiating spermatogonial differentiation. Specific aim 3: Examine the onset of meiosis and establishment of the cycle of the seminiferous epithelium in models where the retinoid metabolism has been perturbed. The hypothesis requires that gonocytes and spermatogonia do not have access to circulating retinoic acid except that which is delivered by the Sertoli cells. Another requirement is that the delivery of retinoic acid to gonocytes or spermatogonia is sufficient to push these cells into the differentiation pathway. This hypothesis suggests a mechanism for entry into meiosis and thus predicts how the cycle of the seminiferous epithelium can be generated and regulated. This research project could potentially determine the molecular mechanisms that initiate spermatogenesis in the male germline and determine the role of the Sertoli cells in that process. Results from these studies could lead to new fundamental approaches to problems relating to male infertility and contraception. This research project could potentially determine the molecular mechanisms that initiate spermatogenesis in the male germline and determine the role of the Sertoli cells in that process. Results from these studies could lead to new fundamental approaches to problems relating to male infertility and contraception.