EXTERNAL GENITALIA DEVELOPMENT AND HYPOSPADIAS

外生殖器发育和尿道下裂

• 批准号: 8435454
• 负责人: Liang Ma
• 金额: $ 29.68万
• 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/8435454
• 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）：包括尿道下裂在内的生殖器畸形是继心脏缺陷之后第二常见的男性出生缺陷。在过去 40 年中，尿道下裂的发病率与其他男性生殖问题一样增加了一倍。人们怀疑胎儿接触内分泌干扰物可能是导致这种增加的原因。然而，我们对尿道下裂的病因或生殖器发育的总体了解仍然非常有限。我们的初步研究令人信服地证明了两种信号通路Shh和Wnt在外生殖器发育的早期雄激素非依赖性阶段和晚期性二态性阶段的重要性。在早期生殖器结节 (GT) 发育过程中，当尿道上皮中的经典 Wnt 通路受到干扰时，就会出现严重的生殖器畸形。在外胚层 2-连环蛋白敲除和生殖器雄性化过程中缺乏 2-连环蛋白的小鼠中观察到尿道下裂样表型。更重要的是，我们的初步数据揭示了 Wnt 拮抗剂的性别二态性表达以及 Shh 和 Wnt 通路在男性外生殖器男性化过程中的功能作用。这些令人兴奋的结果解决了一个涉及非性腺和本地产生的男性因素的高度研究不足的领域，例如介导两性外生殖器发育的生长因子信号级联。基于这些观察，该提案将继续揭示调节生殖器发育和男性化的信号级联，重点关注Shh和Wnt通路。在目标 I 中，我们将通过尝试用 FGF8 修复 Wnt 突变体中的 GT 缺陷来测试 Fgf8 是 GT 发育过程中 Wnt 信号转导的直接靶点的假设。外胚层 2-连环蛋白在 GT 形态发生中的作用也将被研究。在目标 II 中，我们将通过详细分析 Shh 和平滑条件敲除 GT 表型来检验 GT 模式化过程中多个步骤需要 Shh 的假设。将描述 GT 中的 Shh 响应组织，并研究 Shh 和 Wnt 通路之间的相互作用。最后，在目标 III 中，我们将通过分析几个条件敲除突变体的 GT 表型来检验 Wnt/Shh 信号传导参与外生殖器性二态性发育调节的假设。我们的长期目标是利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（例如尿道下裂）的病因学。公共健康相关性：该项目拟研究两条信号通路（Shh 和 Wnt）在外生殖器发育的早期雄激素非依赖性阶段和晚期性二态性阶段的功能。包括尿道下裂在内的生殖器畸形的发生率非常高，但其病因仍然很大程度上未知。该项目将使用几只条件敲除小鼠，揭示这两个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如何相互作用来调节生殖器形态发生和男性化。我们的研究将极大地有助于了解外生殖器发育和尿道下裂的病因学。

项目成果

Genetic interactions of the androgen and Wnt/beta-catenin pathways for the masculinization of external genitalia.

雄激素和 Wnt/β-连环蛋白途径的遗传相互作用对外生殖器男性化的影响。

• DOI: 10.1210/me.2008-0478
• 发表时间: 2009-05-01
• 期刊: Molecular endocrinology
• 作者: S. Miyagawa;Yoshihiko Satoh;Ryuma Haraguchi;Kentarou Suzuki;T. Iguchi;M. Taketo;N. Nakagata;Takahiro Matsumoto;K. Takeyama;S. Kato;G. Yamada
• 通讯作者: G. Yamada

Essential roles of epithelial bone morphogenetic protein signaling during prostatic development.

上皮骨形态发生蛋白信号在前列腺发育过程中的重要作用。

• 发表时间: 2014-07
• 影响因子: 4.8
• 作者: Omori, Akiko;Miyagawa, Shinichi;Ogino, Yukiko;Harada, Masayo;Ishii, Kenichiro;Sugimura, Yoshiki;Ogino, Hajime;Nakagata, Naomi;Yamada, Gen
• 通讯作者: Yamada, Gen

The cessation of gastrulation: BMP signaling and EMT during and at the end of gastrulation.

原肠胚形成的停止：原肠胚形成期间和结束时的 BMP 信号传导和 EMT。

• 发表时间: 2010-07
• 影响因子: 3.2
• 作者: Ohta, Sho;Schoenwolf, Gary C;Yamada, Gen
• 通讯作者: Yamada, Gen

Reduced BMP signaling results in hindlimb fusion with lethal pelvic/urogenital organ aplasia: a new mouse model of sirenomelia.

BMP 信号传导减少导致后肢融合并伴有致命的盆腔/泌尿生殖器官发育不全：一种新的小鼠模型。

• 发表时间: 2012
• 影响因子: 3.7
• 作者: Suzuki, Kentaro;Adachi, Yasuha;Numata, Tomokazu;Nakada, Shoko;Yanagita, Motoko;Nakagata, Naomi;Evans, Sylvia M;Graf, Daniel;Economides, Aris;Haraguchi, Ryuma;Moon, Anne M;Yamada, Gen
• 通讯作者: Yamada, Gen

The hedgehog signal induced modulation of bone morphogenetic protein signaling: an essential signaling relay for urinary tract morphogenesis.

刺猬信号诱导骨形态发生蛋白信号传导的调节：尿路形态发生的重要信号传递中继。

• 发表时间: 2012
• 影响因子: 3.7
• 作者: Haraguchi, Ryuma;Matsumaru, Daisuke;Nakagata, Naomi;Miyagawa, Shinichi;Suzuki, Kentaro;Kitazawa, Sohei;Yamada, Gen
• 通讯作者: Yamada, Gen