Molecular Basis of Sexually Dimorphic Development of the Genital Tubercle

生殖结节性别二态性发育的分子基础

基本信息

批准号：
10362116
负责人：
Xue Sean Li
金额：
$ 34.56万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

项目摘要

An important feature of mammals is the sexually dimorphic reproductive tracts, which include external and internal sex organs. Abnormal development of the genital tubercle (GT), the common embryonic precursor of both male and female external genitalia, frequently results in birth defects including ambiguous genitalia and hypospadias but the underlying molecular basis is poorly understood. This proposal focuses on formation of the external genitalia, a significantly understudied area of embryology. Based on our preliminary data, we hypothesize that, in addition to the gonad-derived sex hormones such as androgens, Wnts expressed from the GT epithelium function as the permissive signal and; following the Wnt and androgen stimulation the gender-specific genomic activity of GT mesenchyme leads to formation of gender-specific external genital structures. We have designed three specific aims to test this hypothesis: 1) to examine whether Wnt4 is the permissive signal for dimorphic GT differentiation; 2) to determine whether sex hormones reprogram the GT- specific landscape of transcription enhancers to control dimorphic gene expression; and 3) to identify critical GT-specific downstream effectors of sex hormones that induce dimorphic GT differentiation to form penis in males and clitoris in females. We have developed and validated a suite of innovative genetic and genomic tools in order to achieve these specific aims. Findings from the proposed studies are expected to improve our understanding of sexual dimorphism in mammals, and to shed new light on the pathogenesis of common birth defects including ambiguous genitalia and hypospadias.

哺乳动物的一个重要特征是两性生殖道，包括外部生殖道和生殖道。内部性器官。生殖器结节 (GT) 发育异常，这是常见的胚胎前体男性和女性的外生殖器，经常导致出生缺陷，包括性别不明的生殖器和尿道下裂，但其潜在的分子基础尚不清楚。该提案的重点是形成外生殖器是胚胎学中一个未被充分研究的领域。根据我们的初步数据，我们假设，除了性腺衍生的性激素（例如雄激素）之外，Wnts 还表达于 GT 上皮发挥许可信号的作用；在 Wnt 和雄激素刺激后 GT间充质的性别特异性基因组活性导致性别特异性外生殖器的形成结构。我们设计了三个具体目标来检验这个假设：1）检验Wnt4是否是二态性 GT 分化的许可信号； 2) 确定性激素是否重新编程GT- 控制二态性基因表达的转录增强子的特定景观； 3) 识别关键性激素的 GT 特异性下游效应物诱导二态性 GT 分化以形成阴茎男性的阴蒂和女性的阴蒂。我们开发并验证了一套创新的遗传和基因组技术工具以实现这些特定目标。拟议研究的结果预计将改善我们的了解哺乳动物的性别二态性，并为共同生育的发病机制提供新的线索缺陷包括生殖器不明确和尿道下裂。