EXTERNAL GENITALIA DEVELOPMENT AND HYPOSPADIAS

外生殖器发育和尿道下裂

• 批准号: 8265869
• 负责人: Liang Ma
• 金额: $ 30.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265869
• 关键词: Address; Androgens; Applications Grants; Area; Attention; Back; Characteristics; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; Disease; Embryo; Embryonic Development; Endocrine Disruptors; Epithelial; Epithelium; Etiology; Event; Exposure to; FGF8 gene; Fetal Diseases; Frequencies; Gene Expression Regulation; Genetic; Genital system; Goals; Growth Factor; Health; Hormonal; Human; Hypospadias; Incidence; Knock-out; Knockout Mice; Mammals; Masculine; Mediating; Mesenchymal; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Organ; Pathway interactions; Pattern; Perinatal Exposure; Phase; Phenotype; Play; Process; Proteins; Regulation; Research Personnel; Role; Series; Sexual Development; Signal Pathway; Signal Transduction; System; Testing; Testis; Tissues; Urethra; base; external genitalia; human SMO protein; loss of function mutation; male; malformation; mutant; prepuce; reproductive; response

DESCRIPTION (provided by applicant): Genital malformation including hypospadias represents the second most common male birth defect after cardiac defect. In the past 40 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, our understandings of the etiology of hypospadias or genital development in general are still very limited. Our preliminary studies convincingly demonstrated that the importance of two signaling pathways, Shh and Wnt in both early androgen-independent and late sexually dimorphic phases of external genitalia development. When the canonical Wnt pathway is perturbed in the urethral epithelium during early genital tubercle (GT) development, severe genital malformations developed. Hypospadias-like phenotype is observed in ectodermal 2-catenin knockouts and in mice lacking 2-catenin during genital masculinization. More importantly, our preliminary data revealed sexually dimorphic expression of Wnt-antagonists and the functional roles of Shh and Wnt pathways during the masculinization of male external genitalia. These exciting results address a highly understudied area involving non-gonadal and locally produced masculine factors, such as growth factor signaling cascade in mediating sexually dimorphic external genital development. Based on these observations, this proposal will continue to uncover the signaling cascade regulating genital development and masculinization, focusing on Shh and Wnt pathways. In aim I, we will test the hypothesis that Fgf8 is a direct target of Wnt signaling during GT development by attempting to rescue GT defects in Wnt mutants with FGF8. The role of ectodermal 2-catenin in GT morphogenesis will also be studied. In aim II, we will test the hypothesis that Shh is required at multiple steps during GT patterning by analyzing in detail Shh and Smoothened conditional knockout GT phenotype. Shh-responding tissues in the GT will be delineated and the interaction between Shh and Wnt pathway will be studied. Finally in aim III, we will test the hypothesis that Wnt/Shh signaling is involved in the regulation of sexually dimorphic development of external genitalia by analyzing GT phenotype of several conditional knockout mutants. 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. PUBLIC HEALTH RELEVAVANCE: This project proposes to study the function of two signaling pathways, Shh and Wnt, in both early androgen-independent and late sexually dimorphic phases of external genitalia development. Genital malformations including hypospadias occur at a very high rate but their etiology remains largely unknown. Using several conditional knockout mice, this project will reveal the downstream signaling events of these two important pathways and how they interact with each other and the androgen signaling pathway to regulate genital morphogenesis and masculinization. Our studies will contribute greatly to the understanding of external genitalia development and the etiology of hypospadias.

描述（由申请人提供）：包括催生包括的生殖器畸形代表了仅次于心脏缺陷的第二常见男性出生缺陷。在过去的40年中，Hypospadias发病率与其他男性生殖问题增加了一倍。怀疑胎儿暴露于内分泌干扰物可能导致了这种增加。但是，我们对催生或生殖器发育的病因的理解仍然非常有限。我们的初步研究令人信服地表明，在早期与雄激素非依赖性和晚期性二态性阶段的两种信号通路SHH和WNT的重要性。当生殖器结节（GT）发育期间尿道上皮的规范WNT途径会扰动时，就会形成严重的生殖器畸形。在外胚层2-catenin敲除和生殖器男性化期间缺乏2-catenin的小鼠中观察到催生性表型。更重要的是，我们的初步数据揭示了Wnt-Antagonists的性表达以及在男性外生殖器男性化过程中SHH和WNT途径的功能作用。这些令人兴奋的结果涉及一个涉及非冈达尔和局部产生的男性因素的高度研究的区域，例如在介导性二态外部生殖器发育时的生长因子信号传导级联。基于这些观察结果，该建议将继续揭示调节生殖器发育和男性化的信号级联，重点是SHH和WNT途径。在AIM I中，我们将通过试图挽救具有FGF8的Wnt突变体中的GT缺陷来检验FGF8是WNT信号传导的直接靶标。外胚层2-catenin在GT形态发生中的作用也将进行研究。在AIM II中，我们将通过详细分析SHH并平滑条件敲除GT表型来检验以下假设，即在GT模式期间需要多个步骤。将划定GT中的SHH反应组织，并研究SHH和WNT途径之间的相互作用。最后，在AIM III中，我们将通过分析几种条件敲除突变体的GT表型来测试Wnt/SHH信号传导与外部生殖器的性二态发育有关的假设。我们的长期目标是使用小鼠分子遗传学来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Hypospadias。公共卫生相关：该项目提议研究外部生殖器发展的早期独立和晚期二态阶段的两个信号通路SHH和WNT的功能。包括催生在内的生殖器畸形以很高的速度发生，但其病因仍然很大。使用几个条件敲除小鼠，该项目将揭示这两种重要途径的下游信号传导事件，以及它们如何相互作用以及雄激素信号传导途径，以调节生殖器形态发生和男性化。我们的研究将有助于理解外部生殖器发展和催眠术的病因。