GENITALIA OUTGROWTH AND HYPOSPADIAS

摘要 包括尿道下裂在内的生殖器畸形是第二大常见的男性出生缺陷， 心脏缺陷在过去的50年里，尿道下裂的发病率增加了沿着，随着其他男性生殖 问题人们怀疑胎儿暴露于内分泌干扰物可能导致了这种增加。 然而，尿道下裂的病因仍然很大程度上不清楚。环境和遗传因素都是 涉案事实上，我们对生殖器发育的理解总体上仍然非常有限。一个完整 了解控制生殖器发育和雄性化的遗传途径， 这些导致生殖器畸形的途径将有巨大的应用，以改善全球健康。在 在过去的几年里，我们对100名男性生殖器结节（GT）的发育进行了全面的遗传分析， 在小鼠体内建立了Wnt/β-catenin β Sp8 → Fgf8的保守遗传通路 附属物生长，包括四肢和外生殖器。Wnt和Shh之间的遗传相互作用 还描述了调节生殖器生长和雄性化的途径。在一起， 这些研究为理解胚胎后期发育以及 环境因素会影响生殖器发育并导致尿道下裂。根据这些发现， 这项建议将继续使用小鼠遗传学，包括一系列条件突变小鼠， 调节GT生长的新遗传途径。在目的I中，我们将表征几种敲除小鼠模型 来建立一个调节GT生长和模式的遗传途径。在Aim II中，我们将使用一种新颖且高度 创新的Split DamID技术用于识别雄激素受体和β-连环蛋白的体内下游靶点 在生殖器男性化过程中。这些研究加在一起，应该会大大提高我们对生殖器的理解 发育和尿道下裂形成。我们的长期目标是利用小鼠分子遗传学， 了解生殖器发育和男性化的过程以及生殖器畸形的病因， 例如尿道下裂。

Abstract Genital malformation including hypospadias represents the second most common male birth defect after cardiac defect. In the past 50 years, hypospadias incidence has doubled along with other male reproductive problems. It is suspected that fetal exposure to endocrine disruptors may have contributed to this increase. However, the etiology of hypospadias is still largely unclear. Both environmental and genetic factors are involved. In fact, our understandings of genital development in general are still very limited. A complete understanding of genetic pathways governing genital development and masculinization and how perturbations of these pathways lead to genital malformations will have immense applications to improve global health. In the past few years, we have performed comprehensive genetic analyses on genital tubercle (GT) development in the mouse and established a conserved genetic pathway (Wnt/β-cateninSp8Fgf8) in regulating body appendage outgrowth, including limbs and external genitalia. Genetic interactions between Wnt and Shh pathways in regulating both genitalia outgrowth and masculinization have also been described. Together, these studies laid the foundation for understanding posterior embryonic development as well as how environmental factors can influence genitalia development and cause hypospadias. Based on these findings, this proposal will continue to use mouse genetics including a series of conditional mutant mice to investigate a novel genetic pathway regulating GT outgrowth. In Aim I, We will characterize several knockout mouse models to build a genetic pathway regulating GT outgrowth and patterning. In Aim II, we will use a novel and highly innovative Split DamID technique to identify in vivo downstream targets of androgen receptor and β-catenin during genital masculinization. Together, these studies should greatly improve our understanding of genitalia development and hypospadias formation. Our long term goal is to use mouse molecular genetics to understand the process of genital development and masculinization and the etiology of genital malformations, such as hypospadias.