GENE DOSAGE IN MAMMALIAN SEXUAL DEVELOPMENT

哺乳动物性发育中的基因剂量

• 批准号: 8171085
• 负责人: Eric J. Vilain
• 金额: $ 0.61万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171085
• 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; 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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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。由于我们的初步结果表明，小鼠11号染色体的同源区域可以防止C57 BL/6 J-YPOS模型中的性逆转，因此我们将测试以下假设：该同源区域携带一个或多个C57 BL/6 J与供体之间存在差异的基因同源片段，并且该差异是保护的原因。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。公共卫生关系：我们生命中最具决定性的时刻之一是，在子宫里，我们走上了男性或女性的道路，触发这一时刻的是当基因Sry在男性中打开时，或者在女性中保持关闭;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，性发育中断的发生频率为0.5%至1%。由于只有25%的人类性别决定的病理基因解释，我们建议确定新的基因参与这一过程，通过使用小鼠模型的异常性发育。该提案将阐明关于男性和女性如何变得不同的基本问题，并将改进先天性性发育障碍患者的遗传分类和诊断方法。