R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis
R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis
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DOI：
10.1242/dev.013359
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发表时间：
2008-03-15
期刊：
影响因子：
4.6
通讯作者：
Whitsett, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Bell, Sheila M.;Schreiner, Claire M.;Whitsett, Jeffrey A.
在此，我们证明了Lrp 6介导的R-spondin 2信号通过经典的Wnt途径是呼吸道和四肢的正常形态发生所必需的。我们发现，无脚插入突变创建一个严重的亚型R-spondin 2等位基因（Rspo 2（Tg））。由Rspo 2（Tg）编码的预测蛋白既不结合细胞表面也不激活经典的Wnt信号报告基因TOPFLASH。TOPFLASH的Rspo 2激活依赖于Lrp 6的第二个EGF样重复序列。Rspo 2（Tg/Tg）小鼠的喉气管软骨、四肢和腭部有严重畸形，肺发育不全与Rspo 2表达部位一致。Rspo 2（Tg/Tg）肺缺陷与分支减少、TOPGAL报告基因活性降低和下游Wnt靶点Irx 3表达降低相关。Rspo 2（Tg）和Lrp 6（-）等位基因的杂交导致更严重的缺陷，包括显着的肺发育不全和气管支气管环，喉结构和所有肢体骨骼元素的缺乏。
Herein, we demonstrate that Lrp6-mediated R-spondin 2 signaling through the canonical Wnt pathway is required for normal morphogenesis of the respiratory tract and limbs. We show that the footless insertional mutation creates a severe hypomorphic R-spondin 2 allele (Rspo2(Tg)). The predicted protein encoded by Rspo2(Tg) neither bound the cell surface nor activated the canonical Wnt signaling reporter TOPFLASH. Rspo2 activation of TOPFLASH was dependent upon the second EGF-like repeat of Lrp6. Rspo2(Tg/Tg) mice had severe malformations of laryngeal-tracheal cartilages, limbs and palate, and lung hypoplasia consistent with sites of Rspo2 expression. Rspo2(Tg/Tg) lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3. Interbreeding the Rspo2(Tg) and Lrp6(-) alleles resulted in more severe defects consisting of marked lung hypoplasia and absence of tracheal-bronchial rings, laryngeal structures and all limb skeletal elements.