Gene Dosage in Mammalian Sexual Development

哺乳动物性发育中的基因剂量

• 批准号: 7673188
• 负责人: Eric J. Vilain
• 金额: $ 38万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673188
• 关键词: Address; Alleles; Animal Model; Area; Candidate Disease Gene; Chromosomes, Human, Pair 11; Classification; Clinical Management; Clitoris; Complex; Cryptorchidism; Data; Defect; Development; Diagnostic; Diagnostic Procedure; Disease; Dose; Embryo; Event; Female; Follistatin; Frequencies; Functional disorder; Funding; Gender Issues; Gene Dosage; Gene Transfer Techniques; Genes; Genetic; Genital system; Genitalia; Genomics; Goals; Gonadal structure; Hermaphroditism; House mice; Human; Human Pathology; Hypertrophy; Hypospadias; Life; Link; Mammals; Minor; Modeling; Modification; Molecular; Molecular Profiling; Morphology; Mouse Strains; Mus; Mus musculus domesticus; Nature; Operative Surgical Procedures; Organism; Other Genetics; Outcome; Outcome Study; Ovary; Pathologic Processes; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Process; Research; Role; Route; Sex Characteristics; Sexual Development; Testicular Tissue; Testing; Testis; Time; Uterus; Variant; Y Chromosome; base; congenic; external genitalia; gonad function; improved; in vivo; male; malformation; molecular marker; mouse model; novel; prevent; protective effect; public health relevance; sex; sex determination; sex development disorder; sry Genes; transcription factor

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. 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.

描述（由申请人提供）：在哺乳动物中，性别确定是胚胎过程，它决定了双能性腺的发育命运到睾丸或卵巢中。它是由男性的存在或女性中的存在触发的，sry是一个编码转录因子的y连锁基因。人类性别确定的疾病会导致性腺功能缺陷，并可能导致内部和外生殖器异常，从轻度的性歧义到完全的性逆转。尽管在人类和小鼠模型中已经确定了几种性别确定的基因，但绝大多数具有性别确定疾病的XY患者尚未在遗传上解释，这表明在此过程中存在其他遗传因素。另外，对已知性别确定基因的分子机制知之甚少。我们的总体目标是破译胚胎性腺分化的分子事件，从而解读性别确定过程。为了实现这一目标，我们将研究性别发展疾病的小鼠模型。我们将确定在C57BL/6J-epos小鼠模型中保护XY性别逆转的新型遗传因素，其中源自家畜菌株（YPOS）和C57BL/6J背景的A Y染色体的组合导致了破坏的测试发育。由于我们的初步结果表明，小鼠染色体的一个先天区域可在C57BL/6J-ippos模型中保护性逆转，因此我们将检验以下假设：该持股区带有一个或几个基因，这些基因具有C57BL/6J和捐赠者，捐赠者，含量，碎片和差异的差异，并且负责保护的差异。我们将通过创建亚军区域并确定与保护表型相关的最小偏见（AIM 1）来缩小先天区域的范围。我们还将筛选并选择候选基因，研究其表达谱以及它们与已知的性别确定基因的功能关系，并测试其表达的改变是否在胚胎性腺发育中引起修饰（AIM 2）。最后，我们将研究C57BL/6J-YPOS模型中XY性逆转的分子机制，并分析先天性区域对性腺发育中保护作用的分子和细胞性质（AIM 3）。剖析哺乳动物性别确定的分子途径对于理解性腺发育中的基本性别差异以及性别发展的人类疾病的病理生理学至关重要。公共卫生相关性：我们一生中最明确的时刻之一是，在子宫中，我们踏上了男性或女性的道路，而这一刻触发的是，雄性中的基因被打开或留在女性中；然而，许多分子事件在SRY作用之后发生的许多分子事件仍然很少理解，在人类中，性发育的破坏发生的频率为0.5％至1％。由于从遗传上说明了人类性别确定的人类病理的25％，因此我们建议通过使用异常性别发展的小鼠模型来鉴定在此过程中涉及的新基因。该提案将阐明有关男性和女性如何不同的基本问题，并将改善患有性发展疾病的患者的遗传分类和诊断方法。