Wntless is required for peripheral lung differentiation and pulmonary vascular development.
Wntless is required for peripheral lung differentiation and pulmonary vascular development.
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DOI：
10.1016/j.ydbio.2013.03.010
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发表时间：
2013-07-01
影响因子：
2.7
通讯作者：
Sinner, Debora
中科院分区：
文献类型：
--
作者：
Cornett, Bridget;Snowball, John;Varisco, Brian M.;Lang, Richard;Whitsett, Jeffrey;Sinner, Debora
Wntless（Wls）是一种在动物界高度保守的基因，编码介导Wnt配体分泌的跨膜蛋白。Wls在发育中的肺中表达，其中Wnt信号传导是肺形态发生所必需的。我们假设Wls在肺发育过程中调节Wnt信号传导中起关键作用，因此影响肺形态发生的关键过程。我们利用Shh-Cre和Dermo 1-Cre小鼠分别在胚胎呼吸上皮和间充质中删除Wls，产生了条件性Wls突变小鼠。Wls的上皮缺失破坏了肺分支形态发生、外周肺发育和肺内皮分化。上皮细胞Wls突变小鼠在出生时由于肺发育不全和肺出血引起的呼吸衰竭而死亡。在这些小鼠的肺中，介导血管发育的VEGF和Tie 2-血管生成素信号通路从发育的早期阶段下调。相反，发育中的肺的间充质细胞中Wls的缺失并不改变分支形态发生或早期间充质分化。体外试验支持Wls部分通过Wnt 5a调节肺血管发育的概念。我们的结论是，上皮Wls调节Wnt配体的活动，肺血管分化和外周肺形态发生的关键。这些研究为理解正常肺血管形成和与先天性肺病相关的畸形肺血管发育的分子机制提供了新的框架。
Wntless (Wls), a gene highly conserved across the animal kingdom, encodes for a transmembrane protein that mediates Wnt ligand secretion. Wls is expressed in developing lung, wherein Wnt signaling is necessary for pulmonary morphogenesis. We hypothesize that Wls plays a critical role in modulating Wnt signaling during lung development and therefore affects processes critical for pulmonary morphogenesis. We generated conditional Wls mutant mice utilizing Shh-Cre and Dermo1-Cre mice to delete Wls in the embryonic respiratory epithelium and mesenchyme, respectively. Epithelial deletion of Wls disrupted lung branching morphogenesis, peripheral lung development and pulmonary endothelial differentiation. Epithelial Wls mutant mice died at birth due to respiratory failure caused by lung hypoplasia and pulmonary hemorrhage. In the lungs of these mice, VEGF and Tie2-angiopoietin signaling pathways, which mediate vascular development, were downregulated from early stages of development. In contrast, deletion of Wls in mesenchymal cells of the developing lung did not alter branching morphogenesis or early mesenchymal differentiation. In vitro assays support the concept that Wls acts in part via Wnt5a to regulate pulmonary vascular development. We conclude that epithelial Wls modulates Wnt ligand activities critical for pulmonary vascular differentiation and peripheral lung morphogenesis. These studies provide a new framework for understanding the molecular mechanisms underlying normal pulmonary vasculature formation and the dysmorphic pulmonary vasculature development associated with congenital lung disease.
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影响因子：
11.8
作者：
Corada M;Nyqvist D;Orsenigo F;Caprini A;Giampietro C;Taketo MM;Iruela-Arispe ML;Adams RH;Dejana E
通讯作者：
Dejana E
DOI：
10.1165/ajrcmb.27.2.4703
发表时间：
2002-08-01
影响因子：
6.4
作者：
Galambos, C;Ng, YS;deMello, DE
通讯作者：
deMello, DE
影响因子：
1.5
作者：
Engert, Silvia;Liao, W. Perry;Lickert, Heiko
通讯作者：
Lickert, Heiko
影响因子：
2.7
作者：
Goss AM;Tian Y;Cheng L;Yang J;Zhou D;Cohen ED;Morrisey EE
通讯作者：
Morrisey EE
影响因子：
9.2
作者：
Cha, Sang-Wook;Tadjuidje, Emmanuel;Heasman, Janet
通讯作者：
Heasman, Janet