Anorectal malformations caused by defects in sonic hedgehog signaling
Anorectal malformations caused by defects in sonic hedgehog signaling
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DOI：
10.1016/s0002-9440(10)61747-6
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发表时间：
2001-08-01
影响因子：
6
通讯作者：
Kim, PCW
中科院分区：
文献类型：
--
作者：
Mo, R;Kim, JH;Kim, PCW
肛门直肠畸形是影响婴儿远端后肠发育的常见临床问题。肛门直肠畸形的范围从轻度狭窄的肛门到闭锁的肛门并伴有尿路和肠道之间的瘘管，再到最严重的形式--永久性泄殖腔。肛门直肠畸形的病因、胚胎学和发病机制尚不清楚，也存在争议。Sonic hedgehog(Shh)是一种来自内胚层的信号分子，可诱导鸡后肠中胚层基因的表达。然而，Shh信号在哺乳动物后肠发育中的作用尚不清楚。在这里，我们显示在Shh信号通路中有各种缺陷的突变小鼠表现出类似于人类肛门直肠的远端后肠缺陷谱。畸形。Shh零突变小鼠表现出永久性泄殖腔。缺失Gli2或Gli3的突变小鼠表现为肛门闭锁、直肠尿瘘和肛门狭窄。Gli2和Gli3分别是参与Shh信号转导的两个锌指转录因子。此外，在Gli2(-/-)、Gli3(+/-)、Gli2(+/-)、Gli3(-/-)和Gli2(-/-)；Gli3(-/-)小鼠中也观察到持续泄殖腔，表现出基因剂量依赖效应。因此，Shh信号对远端的正常发育是必不可少的。小鼠的后肠和影响Shh信号的突变产生了一系列肛门直肠畸形，这可能揭示出对它们与人类疾病等价物的新见解。
Anorectal malformations are a common clinical problem affecting the development of the distal hindgut in infants. The spectrum of anorectal malformations ranges from the mildly stenotic anus to imperforate anus with a fistula between the urinary and intestinal tracts to the most severe form, persistent cloaca. The etiology, embryology, and pathogenesis of anorectal malformations are poorly understood and controversial. Sonic hedgehog (Shh) is an endoderm-derived signaling molecule that induces mesodermal gene expression in the chick hindgut. However, the role of Shh signaling in mammalian hindgut development is unknown. Here, we show that mutant mice with various defects in the Shh signaling pathway exhibit a spectrum of distal hindgut defects mimicking human anorectal. malformations. Shh null-mutant mice display persistent cloaca. Mutant mice lacking Gli2 or Gli3, two zinc finger transcription factors involved in Shh signaling, respectively, exhibit imperforate anus with recto-urethral fistula and anal stenosis. Furthermore, persistent cloaca is also observed in Gli2(-/-); Gli3(+/-), Gli2(+/-);Gli3(-/-), and Gli2(-/-);Gli3(-/-) mice demonstrating a gene dose-dependent effect. Therefore, Shh signaling is essential for normal development of the distal. hindgut in mice and mutations affecting Shh signaling produce a spectrum of anorectal malformations that may reveal new insights into their human disease equivalents.