Dysregulation of Wnt inhibitory factor 1 (Wif1) expression resulted in aberrant Wnt-β-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations.
Dysregulation of Wnt inhibitory factor 1 (Wif1) expression resulted in aberrant Wnt-β-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations.
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Wnt抑制因子1（WIF1）表达的失调导致内胚层内胚层的异常Wnt-β-catenin信号传导和细胞死亡以及肛门直肠畸形。
DOI：
10.1038/cdd.2014.20
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发表时间：
2014-06
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
在哺乳动物尿直肠发育中，尿直肠隔（urs）从腹侧体壁下降到泄殖腔膜（cm），将泄殖腔分隔为尿生殖窦和直肠。先天性肛门直肠畸形（ARMs）是由先天性肛门直肠发育不良引起的，其发病机制尚不清楚.最近的研究仅集中在urs间充质增殖的重要性，这是由内胚层来源的Sonic Hedgehog（Shh）诱导的。在这里，我们表明，程序性细胞死亡的顶端urs和近端cm内胚层是特别重要的urs的生长在分隔。凋亡内胚层与Wnt抑制因子1（Wnt-β-catenin信号传导抑制剂）的时空表达密切相关。在Wif 1 lacZ/lacZ突变小鼠和培养的含外源性Wif 1的泌尿直肠中，泄殖腔分隔缺陷，表现为隐睾和尿道下裂样表型，这种分隔缺陷也在Shh−/−突变体和内胚层β-连环蛋白功能获得性（GOF）突变体中观察到。此外，Wif 1和Shh在泄殖腔内胚层中以互补的方式表达，并且Wif 1在与Shh-/-突变体中过度的内胚层凋亡和分隔缺陷相关的urs和cm中异位表达。此外，内胚层β-catenin GOF突变体胚胎中的凋亡细胞显著减少，这抵消了Wif 1的抑制作用。总而言之，这些数据表明，调控表达的Wif 1是至关重要的泄殖腔分隔期间的urs的增长。因此，Wif 1通过抑制β-catenin信号来调控尿内胚层的细胞凋亡，这可能有助于下面的增殖间充质细胞向cm突出以形成泄殖腔分隔。这种内胚层Shh-Wif 1-β-连环蛋白信号传导轴的失调有助于ARM发病机制。
In mammalian urorectal development, the urorectal septum (urs) descends from the ventral body wall to the cloaca membrane (cm) to partition the cloaca into urogenital sinus and rectum. Defective urs growth results in human congenital anorectal malformations (ARMs), and their pathogenic mechanisms are unclear. Recent studies only focused on the importance of urs mesenchyme proliferation, which is induced by endoderm-derived Sonic Hedgehog (Shh). Here, we showed that the programmed cell death of the apical urs and proximal cm endoderm is particularly crucial for the growth of urs during septation. The apoptotic endoderm was closely associated with the tempo-spatial expression of Wnt inhibitory factor 1 (Wif1), which is an inhibitor of Wnt-β-catenin signaling. In Wif1lacZ/lacZ mutant mice and cultured urorectum with exogenous Wif1, cloaca septation was defective with undescended urs and hypospadias-like phenotypes, and such septation defects were also observed in Shh−/− mutants and in endodermal β-catenin gain-of-function (GOF) mutants. In addition, Wif1 and Shh were expressed in a complementary manner in the cloaca endoderm, and Wif1 was ectopically expressed in the urs and cm associated with excessive endodermal apoptosis and septation defects in Shh−/− mutants. Furthermore, apoptotic cells were markedly reduced in the endodermal β-catenin GOF mutant embryos, which counteracted the inhibitory effects of Wif1. Taken altogether, these data suggest that regulated expression of Wif1 is critical for the growth of the urs during cloaca septation. Hence, Wif1 governs cell apoptosis of urs endoderm by repressing β-catenin signal, which may facilitate the protrusion of the underlying proliferating mesenchymal cells towards the cm for cloaca septation. Dysregulation of this endodermal Shh-Wif1-β-catenin signaling axis contributes to ARM pathogenesis.
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影响因子：
11.4
作者：
Grotewold, L;Rüther, U
通讯作者：
Rüther, U
DOI：
10.1006/bbrc.1997.7124
发表时间：
1997-08-28
影响因子：
3.1
作者：
Feil, R;Wagner, J;Chambon, P
通讯作者：
Chambon, P
影响因子：
15.9
作者：
Kansara, Maya;Tsang, Michael;Thomas, David M.
通讯作者：
Thomas, David M.
影响因子：
4.6
作者：
Lin, Congxing;Yin, Yan;Ma, Liang
通讯作者：
Ma, Liang
影响因子：
9.8
作者：
Kohlhase, J;Taschner, PEM;Engel, W
通讯作者：
Engel, W