Seifert Ashley W, Bouldin Cortney M, Choi Kyung-Suk, Harfe Brian D, Cohn Martin J
Department of Biology, University of Florida, Cancer/Genetics Research Complex, PO Box 103610, Gainesville, FL 32610-3610, USA.
Development. 2009 Dec;136(23):3949-57. doi: 10.1242/dev.042291.
Malformations of the external genitalia are among the most common congenital anomalies in humans. The urogenital and anorectal sinuses develop from the embryonic cloaca, and the penis and clitoris develop from the genital tubercle. Within the genital tubercle, the endodermally derived urethral epithelium functions as an organizer and expresses sonic hedgehog (Shh). Shh knockout mice lack external genitalia and have a persistent cloaca. This identified an early requirement for Shh, but precluded analysis of its later role in the genital tubercle. We conducted temporally controlled deletions of Shh and report that Shh is required continuously through the onset of sexual differentiation. Shh function is divisible into two temporal phases; an anogenital phase, during which Shh regulates outgrowth and patterning of the genital tubercle and septation of the cloaca, and a later external genital phase, during which Shh regulates urethral tube closure. Disruption of Shh function during the anogenital phase causes coordinated anorectal and genitourinary malformations, whereas inactivation during the external genital phase causes hypospadias. Shh directs cloacal septation by promoting cell proliferation in adjacent urorectal septum mesenchyme. Additionally, conditional inactivation of smoothened in the genital ectoderm and cloacal/urethral endoderm shows that the ectoderm is a direct target of Shh and is required for urethral tube closure, highlighting a novel role for genital ectoderm in urethragenesis. Identification of the stages during which disruption of Shh results in either isolated or coordinated malformations of anorectal and external genital organs provides a new tool for investigating the etiology of anogenital malformations in humans.
外生殖器畸形是人类最常见的先天性异常之一。泌尿生殖窦和肛门直肠窦由胚胎泄殖腔发育而来，阴茎和阴蒂由生殖结节发育而来。在生殖结节内，内胚层来源的尿道上皮作为组织者发挥作用并表达音猬因子（Shh）。Shh基因敲除小鼠缺乏外生殖器且存在持续性泄殖腔。这确定了Shh在早期的需求，但排除了对其在生殖结节后期作用的分析。我们进行了Shh的时间控制缺失实验，并报告Shh在性分化开始前持续发挥作用。Shh的功能可分为两个时间阶段；一个是肛门生殖器阶段，在此期间Shh调节生殖结节的生长和模式以及泄殖腔的分隔，另一个是后期的外生殖器阶段，在此期间Shh调节尿道管的闭合。在肛门生殖器阶段Shh功能的破坏会导致协调性的肛门直肠和泌尿生殖系统畸形，而在外生殖器阶段失活则会导致尿道下裂。Shh通过促进相邻泌尿直肠隔间充质中的细胞增殖来指导泄殖腔分隔。此外，生殖外胚层和泄殖腔/尿道内胚层中 smoothened 的条件性失活表明外胚层是Shh的直接靶点，并且是尿道管闭合所必需的，这突出了生殖外胚层在尿道发生中的新作用。确定Shh破坏导致肛门直肠和外生殖器器官孤立或协调性畸形的阶段，为研究人类肛门生殖器畸形的病因提供了一种新工具。
