Genetic basis of testicular descent

描述（由申请人提供）：隐睾症，或称隐睾症，是新生儿最常见的先天性缺陷之一。如果不及时治疗，这种情况会导致不孕，并大大增加成年后患睾丸癌的机会。本项目的主要目的是建立睾丸发育过程中遗传和生化事件的精确网络。这一建议是基于最近对睾丸激素胰岛素样3及其受体GREAT的鉴定，它们是地方分化的关键调节因子。利用小鼠crsp突变体，我们鉴定了GREAT基因，发现它编码一个G蛋白偶联受体，并证明GREAT是体内唯一的INSL3同源受体。对隐睾患者中这两个基因的突变分析揭示了功能上有害的突变，这可能是导致异常表型的原因。我们实验室生产的一系列转基因小鼠突变体为解决有关INSL3信号在体内的作用和机制的具体问题提供了独特的基础。此外，INSL3受体是一种GPCR，这一事实使其成为未来治疗发展的一个有吸引力的靶点。我们将探讨INSL3信号通路是睾丸下降的关键调节因子的假设。为了验证这一假设，我们提出了以下具体目标：1 .确定在发育过程中导致INSL3/GREAT表达激活的遗传因素；2. 鉴定INSL3调控的下游靶基因；3. 识别INSL3/GREAT信号通路；4. 探讨GREAT受体的激活及其脱敏机制。因此，我们将确定一系列导致睾丸下降的遗传事件，并表征INSL3/GREAT细胞信号传导的机制。所提出的研究将有助于更好地了解睾丸下降及其在男性发育过程中的调节。

DESCRIPTION (provided by applicant): Cryptorchidism, or undescended testis, is one of the most common congenital defect in newborn boys. If left untreated, this condition causes infertility and drastically increases the chance of testicular cancer in adulthood. The key aim of this project is to establish the precise network of genetic and biochemical events underlying testicular descent during development. The proposal is based on recent identification of the testicular hormone Insulin-like 3, and its receptor, GREAT, as the critical regulators of gubernacular differentiation. Using mouse crsp mutant we have identified the GREAT gene, showed that it encodes a G protein-coupled receptor, and demonstrated that GREAT is the only cognate receptor for INSL3 in vivo. Mutation analysis of the two genes in cryptorchid patients revealed functionally deleterious mutations, which may be responsible for the abnormal phenotype. A series of transgenic mouse mutants produced in our laboratory provides a unique basis to address specific questions regarding the role and mechanisms of INSL3 signaling in vivo. Furthermore, the fact, that the INSL3 receptor is a GPCR, makes it an attractive target for future therapeutic development. We are going to explore the hypothesis, that INSL3 signaling pathway is a key regulator of testicular descent. To test this hypothesis we propose the following Specific Aims 1: To identify genetic factors leading to the activation of INSL3/GREAT expression during development; 2. To identify downstream target genes controlled by INSL3; 3. To identify cellular pathways involved in INSL3/GREAT signaling; 4. To determine mechanisms of GREAT receptor activation and its desensitization. As a result, we will identify a sequence of genetic events leading to testicular descent and characterize the mechanisms of INSL3/GREAT cellular signaling. The proposed studies will provide a better understanding of the testicular descent and its regulation during male development.