The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.
The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway.
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DOI：
10.1242/dmm.019083
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发表时间：
2015-06
影响因子：
4.3
通讯作者：
Jagger DJ
中科院分区：
文献类型：
--
作者：
Abdelhamed ZA;Natarajan S;Wheway G;Inglehearn CF;Toomes C;Johnson CA;Jagger DJ
纤毛病是一组表现为多器官异常的发育障碍。TMEM 67（MKS 3）突变导致一系列人类纤毛病，包括Meckel-Gruber和Joubert综合征。在这项研究中，我们描述了Tmem 67 tm 1Dgen/H1基因敲除小鼠的多器官发育异常，这些异常与Wnt 5a和Ror 2基因敲除小鼠中观察到的异常非常相似。这些包括肺发育不全、室间隔缺损、身体纵轴缩短、肢体异常、耳蜗毛细胞静纤毛束定向和基底体/动纤毛定位缺陷。基底体/动纤毛复合体经常从毛束中分离，这表明异常的基底体迁移，尽管Corti器官中的平面细胞极性和顶端平面不对称性是正常的。TMEM 67（meckelin）在用Wnt 5a条件培养基刺激时对于非经典Wnt受体ROR 2（受体酪氨酸激酶样孤儿受体2）的磷酸化是必需的。ROR 2还在睫状过渡区与TMEM 67共定位并相互作用。此外，在体外结合试验中，TMEM 67的细胞外N末端结构域优先与Wnt 5a结合。Tmem 67突变小鼠的培养肺未能响应Wnt 5a的上皮分支形态发生的刺激。Wnt 5a还抑制野生型胚胎肺中的Shh和经典Wnt/β-catenin信号通路。通过激活RhoA刺激Wnt 5a-TMEM 67-ROR 2轴下游的非经典Wnt途径，挽救了肺发育不全表型，包括正确的上皮分支形态发生和细胞极性的丧失。我们认为TMEM 67是一种在非经典Wnt信号传导中起主要作用的受体，由Wnt 5a和ROR 2介导，通常抑制Shh信号传导。因此，Wnt 5a-TMEM 67-ROR 2轴的下游治疗靶向可能减少或预防纤毛病和其他先天性病症中的肺发育不全。突出显示的文章：TMEM 67是非经典Wnt信号传导的受体，涉及发育信号传导期间的Wnt 5a-TMEM 67-ROR 2轴和纤毛病疾病状态的破坏。
Ciliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67tm1Dgen/H1 knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions. Highlighted Article: TMEM67 is a receptor of non-canonical Wnt signalling, implicating the Wnt5a-TMEM67-ROR2 axis during developmental signalling and disruption in ciliopathy disease state.
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