GENE DOSAGE IN MAMMALIAN SEXUAL DEVELOPMENT

哺乳动物性发育中的基因剂量

• 批准号: 7955696
• 负责人: Eric J. Vilain
• 金额: $ 0.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955696
• 关键词: Area; Candidate Disease Gene; Chromosomes, Human, Pair 11; Classification; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Diagnostic Procedure; Disease; Embryo; Event; Female; Frequencies; Functional disorder; Funding; Gene Dosage; Genes; Genetic; Goals; Gonadal structure; Grant; Human; Human Pathology; Institution; Life; Link; Mammals; Modeling; Modification; Molecular; Molecular Profiling; Mus; Nature; Other Genetics; Ovary; Pathway interactions; Patients; Phenotype; Process; Research; Research Personnel; Resources; Sex Characteristics; Sexual Development; Source; Testing; Testis; United States National Institutes of Health; Uterus; Y Chromosome; computational anatomy; congenic; external genitalia; gonad function; improved; male; mouse model; novel; protective effect; public health relevance; sex; sex determination; sex development disorder; sry Genes; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. PUBLIC HEALTH RELEVANCE: One of the most defining moment of our lives is when, in the womb, we embark on a male or female path, and what triggers this moment is when the gene Sry is turned on in males, or stays off in females; yet, many molecular events that happen after Sry action remain poorly understood, and in humans, disruption of sexual development occurs at a frequency of 0.5% to 1%. As only 25% of human pathologies of sex determination are explained genetically, we propose to identify new genes involved in this process by using a mouse model of abnormal sex development. This proposal will elucidate basic questions about how males and females become different, and will improve genetic classification and diagnostic methods of patients born with disorders of sex development.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在哺乳动物中，性别决定是胚胎过程，它决定了双潜能性腺发育到睾丸或卵巢的命运。它是由男性的存在或女性的Sry的存在触发的，Sry是一种编码转录因子的Y连锁基因。人类性别决定的障碍会导致性腺功能的缺陷，并可能导致内外生殖器的一系列异常，从轻度的性别模糊到完全性反转。尽管在人类和小鼠模型中已经发现了几个性别决定基因，但绝大多数患有性别决定障碍的XY患者没有得到遗传解释，这表明这一过程中存在其他遗传因素。此外，已知的性别决定基因的分子机制也知之甚少。我们的首要目标是破译胚胎性腺分化的分子事件，从而破译性别决定过程。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C57BL/6J-YPOS小鼠模型中识别防止XY性反转的新遗传因素，在该模型中，来自家系(YPOS)的Y染色体和C57BL/6J背景相结合会导致睾丸发育中断。由于我们的初步结果显示，在C57BL/6J-YPOS模型中，小鼠11号染色体的同源区域对性反转具有保护作用，因此我们将检验这样的假设，即该同源区域携带C57BL/6J与供体同源片段之间的一个或多个不同的基因，并且这种差异是导致保护的原因。我们将通过创建亚同源区域并识别与保护表型相关的最小同源片段来缩小同源区域(目标1)。我们还将筛选和选择候选基因，研究它们的表达谱以及它们与已知性别决定基因的功能关系，并测试它们的表达变化是否会导致胚胎性腺发育的改变(目标2)。最后，我们将在C57BL/6J-YPOS模型中研究XY性逆转的分子机制，并分析同源区对性腺发育保护作用的分子和细胞性质(目标3)。解剖哺乳动物性别决定的分子途径对于理解性腺发育的基本性别差异和人类性发育障碍的病理生理学将是至关重要的。与公共健康相关：我们生命中最具决定性的时刻之一是当我们在子宫中踏上男性或女性的道路时，触发这一时刻的是男性的Sry基因开启，或者女性的Sry基因保持关闭；然而，Sry作用后发生的许多分子事件仍然知之甚少，在人类中，性发育中断的频率为0.5%到1%。由于只有25%的人类性别决定的病理是从基因上解释的，我们建议通过使用性别发育异常的小鼠模型来识别参与这一过程的新基因。这项建议将阐明有关男性和女性如何变得不同的基本问题，并将改进先天性发育障碍患者的基因分类和诊断方法。