Medical Research Council, Harwell, Oxfordshire OX11 0RD, UK.
Hum Mol Genet. 2010 Jun 1;19(11):2251-67. doi: 10.1093/hmg/ddq104. Epub 2010 Mar 10.
The lungs are generated by branching morphogenesis as a result of reciprocal signalling interactions between the epithelium and mesenchyme during development. Mutations that disrupt formation of either the correct number or shape of epithelial branches affect lung function. This, in turn, can lead to congenital abnormalities such as cystadenomatoid malformations, pulmonary hypertension or lung hypoplasia. Defects in lung architecture are also associated with adult lung disease, particularly in cases of idiopathic lung fibrosis. Identifying the signalling pathways which drive epithelial tube formation will likely shed light on both congenital and adult lung disease. Here we show that mutations in the planar cell polarity (PCP) genes Celsr1 and Vangl2 lead to disrupted lung development and defects in lung architecture. Lungs from Celsr1(Crsh) and Vangl2(Lp) mouse mutants are small and misshapen with fewer branches, and by late gestation exhibit thickened interstitial mesenchyme and defective saccular formation. We observe a recapitulation of these branching defects following inhibition of Rho kinase, an important downstream effector of the PCP signalling pathway. Moreover, epithelial integrity is disrupted, cytoskeletal remodelling perturbed and mutant endoderm does not branch normally in response to the chemoattractant FGF10. We further show that Celsr1 and Vangl2 proteins are present in restricted spatial domains within lung epithelium. Our data show that the PCP genes Celsr1 and Vangl2 are required for foetal lung development thereby revealing a novel signalling pathway critical for this process that will enhance our understanding of congenital and adult lung diseases and may in future lead to novel therapeutic strategies.
肺部是通过分支形态发生产生的，这是发育过程中上皮和间充质之间相互信号作用的结果。破坏上皮分支正确数量或形状形成的突变会影响肺功能。这反过来又会导致先天性异常，如囊性腺瘤样畸形、肺动脉高压或肺发育不全。肺结构的缺陷也与成人肺部疾病有关，特别是在特发性肺纤维化的情况下。确定驱动上皮管形成的信号通路可能会揭示先天性和成人肺部疾病的原因。在这里，我们表明，平面细胞极性（PCP）基因 Celsr1 和 Vangl2 的突变导致肺部发育异常和肺结构缺陷。Celsr1(Crsh) 和 Vangl2(Lp) 小鼠突变体的肺较小且畸形，分支较少，在妊娠晚期表现出增厚的间质和囊状形成缺陷。我们观察到 Rho 激酶抑制剂抑制后会出现这些分支缺陷的重现，Rho 激酶是 PCP 信号通路的重要下游效应物。此外，上皮完整性被破坏，细胞骨架重塑受到干扰，并且突变的内胚层不能正常分支以响应趋化因子 FGF10。我们进一步表明，Celsr1 和 Vangl2 蛋白存在于肺上皮的受限空间域内。我们的数据表明，PCP 基因 Celsr1 和 Vangl2 是胎儿肺发育所必需的，从而揭示了一个新的信号通路，该通路对于这个过程至关重要，这将增强我们对先天性和成人肺部疾病的理解，并可能在未来导致新的治疗策略。
