Novel Signaling Molecules in Wolffian Duct Development and Differentiation

描述（由申请人提供）：沃尔夫管（WD）是雄性内生殖道的祖先，其经历了从简单的管状结构到附睾、输出小管和输精管的形态分化。WD的初始形成与性腺的性别或性腺中产生的激素无关;然而，WD的后期发展需要Leydig细胞来源的雄激素，其作用机制尚不清楚。在人类临床病例和小鼠遗传学研究中充分证明，WD发育缺陷具有灾难性后果，导致两性和生殖恶性肿瘤。为了更好地理解这些先天性疾病的原因和继发性健康影响，有必要了解WD的发展，维持和分化中涉及的一般分子机制。了解WD形成和维持的分子机制; 2）研究WD如何分化为男性生殖道的专门区域。该提案将使用几种遗传小鼠模型（条件性Shh敲除、睾丸雌性化和激活素A敲除），通过原位杂交、大体和组织病理学分析以及免疫细胞化学等方法进行分析。从这项研究中获得的数据对于确定性别分化的正常过程至关重要，这对于了解不孕症，生殖肿瘤和间性是如何产生的至关重要。

DESCRIPTION (provided by applicant): The Wolffian duct (WD) is the progenitor for the male internal reproductive tract, which undergoes morphological differentiation from a simple tube-like structure into the epididymis, efferent ductules, and vas deferens. Initial formation of the WD is independent of the sex of the gonad or hormones produced in the gonads; however, later development of the WD requires Leydig cell-derived androgens, whose mechanisms of action remain unknown. It is well proven in human clinical cases and mouse genetic studies that defects in development of the WD have catastrophic consequences leading to intersex and reproductive malignancy. In order to better comprehend the causes of these congenital disorders and the secondary health effects, it is necessary to understand the general molecular mechanisms involved in the development, maintenance and differentiation of the WD. To understand the molecular mechanisms for formation and maintenance of the WD and 2) investigate how the WD differentiates into specialized regions of the male reproductive tract. This proposal will use several genetic mouse models (conditional Shh knockout, Testicular feminization, and activin A knockout) analyzed by methodologies including in situ hybridization, gross and histopathological analysis, and immunocytochemistry. The data obtained from this research is critical in identifying the normal course of sex differentiation, which is fundamentally important to understand how infertility, reproductive neoplasia, and intersexualilty arise.