Gene Dosage in Mammalian Sexual Development

描述（由申请人提供）：在哺乳动物中，性别决定是决定双能性腺发育成睾丸或卵巢的胚胎过程。它是由男性中存在或女性中不存在Sry（一种编码转录因子的Y连锁基因）触发的。人类性别决定障碍会导致性腺功能缺陷，并可能导致一系列的异常，在内部和外部生殖器，从轻微的性别模糊到完全的性别逆转。虽然在人类和小鼠模型中已经鉴定出几个性别决定基因，但绝大多数XY患者的性别决定障碍无法从遗传学上解释，这表明存在其他参与这一过程的遗传因素。此外，已知的性别决定基因的分子机制知之甚少。我们的首要目标是破译胚胎性腺分化的分子事件，因此性别决定的过程。为了实现这一目标，我们将研究性发育障碍的小鼠模型。我们将在C57 BL/6 J-YPOS小鼠模型中确定防止XY性逆转的新遗传因子，其中来自于一种睾丸炎病毒株（YPOS）的Y染色体和C57 BL/6 J背景的组合导致睾丸发育中断。由于我们的初步研究结果表明，同源区域从小鼠染色体11保护性逆转的C57 BL/6 J-YPOS模型，我们将测试的假设，该同源区域携带一个或几个基因，C57 BL/6 J和供体，同源，片段之间的差异是负责的保护。我们将通过创建亚同源区域并确定与保护表型相关的最小同源片段来缩小同源区域（目的1）。我们还将筛选和选择候选基因，研究其表达谱及其与已知性别决定基因的功能关系，并测试其表达的改变是否会导致胚胎性腺发育的改变（目的2）。最后，我们将在C57 BL/6 J-YPOS模型中研究XY性逆转的分子机制，并分析同源区域对性腺发育的保护作用的分子和细胞性质（目的3）。研究哺乳动物性别决定的分子途径对于了解性腺发育中的基本性别差异和人类性发育障碍的病理生理学至关重要。

DESCRIPTION (provided by applicant): In mammals, sex determination is the embryonic process that determines the developmental fate of the bipotential gonad into either testis or ovary. It is triggered by the presence, in males, or the absence in females, of Sry, a Y-linked gene encoding a transcription factor. Disorders of human sex determination cause defects in gonadal function and can result in a spectrum of abnormalities in the internal and external genitalia, ranging from mild sexual ambiguities to complete sex reversal. Although several sex-determining genes have been identified in humans and mouse models, the vast majority of XY patients with disorders of sex determination are not explained genetically, suggesting the existence of other genetic factors involved in this process. In addition, the molecular mechanisms of known sex-determining genes are poorly understood. Our overarching goal is to decipher the molecular events underlying the differentiation of the embryonic gonad, and therefore the process of sex determination. To achieve this objective, we will investigate a mouse model of disorders of sex development. We will identify novel genetic factors protecting against XY sex reversal in the C57BL/6J-YPOS mouse model in which the combination of a Y chromosome originating from a domesticus strain (YPOS) and a C57BL/6J background results in disrupted testicular development. Since our preliminary results show that a congenic region from mouse chromosome 11 protects against sex reversal in the C57BL/6J-YPOS model, we will test the hypothesis that this congenic region carries one or several genes that differ between C57BL/6J and the donor, congenic, fragment and that the difference is responsible for the protection. We will narrow down the congenic region by creating sub-congenic areas and identifying a minimal congenic fragment associated with the protection phenotype (Aim 1). We will also screen for and select candidate genes, investigate their expression profile and their functional relationship with known sex-determining genes and test if the alteration of their expression causes modifications in embryonic gonadal development (Aim 2). Finally, we will investigate the molecular mechanisms of XY sex reversal in the C57BL/6J-YPOS model and analyze the molecular and cellular nature of protective effect from the congenic region on gonadal development (Aim 3). Dissecting the molecular pathway of mammalian sex determination will be crucial in understanding the basic sex differences in gonadal development and the pathophysiology of human disorders of sex development.