Molecular Basis of Sexually Dimorphic Development of the Genital Tubercle

哺乳动物的一个重要特征是性二态生殖道，它包括外部和 内脏性器官。生殖器结节(GT)发育异常，这是该病常见的胚胎前驱 男性和女性外生殖器，经常导致出生缺陷，包括不明确的生殖器和 但其潜在的分子基础却鲜为人知。这项建议的重点是形成 外生殖器，胚胎学中一个研究很少的领域。根据我们的初步数据，我们 假设，除了性腺衍生的性激素，如雄激素，WNTS表达自 GT上皮起允许信号的作用；在WNT和雄激素刺激后， GT间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的目标来检验这一假设：1)检查WNT4是否是 GT分化的许可信号；2)确定性激素是否重新编程GT- 转录增强子的特定景观来控制二态基因的表达；以及3)识别关键的 性激素的GT特异性下游效应分子诱导GT分化形成阴茎 男性和女性的阴蒂。我们已经开发并验证了一套创新的基因和基因组 工具，以实现这些具体目标。拟议研究的结果有望改善我们的 了解哺乳动物的性别二型性，并为共同出生的发病机制提供新的线索 畸形包括生殖器不清和尿道下裂。

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.