Novel Signaling Molecules in Wolffian Duct Development and Differentiation

描述(申请人提供)：沃尔菲管(WD)是男性内生殖道的前体，它经历了从简单的管状结构到附睾、传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产生的激素无关；然而，WD的后期发展需要间质细胞来源的雄激素，其作用机制尚不清楚。人类临床病例和小鼠遗传学研究充分证明，WD发育缺陷会导致灾难性后果，导致双性和生殖恶性肿瘤。为了更好地了解这些先天性疾病的原因及其对二次健康的影响，有必要了解与WD的发生、维持和分化有关的一般分子机制。为了了解WD的形成和维持的分子机制，以及2)研究WD如何分化为男性生殖道的专门区域。这项建议将使用几种遗传小鼠模型(条件性Shh基因敲除、睾丸女性化和激活素A基因敲除)，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正常的性别分化过程是至关重要的，这对于理解不孕不育、生殖肿瘤和性间性的发生是至关重要的。

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.