Ciliopathies are developmental disorders caused by mutations in components of the primary cilium (a microtubule-based mechanosensor organelle present in many mammalian cells), and are usually characterised by multi-organ abnormalities. Congenital lung malformation (pulmonary hypoplasia) often occurs, and is considered the leading cause of death in Meckel-Gruber syndrome (MKS), a lethal ciliopathy associated with mutations in the transmembrane protein 67 gene, Tmem67. To investigate mechanisms of pulmonary hypoplasia in MKS, Colin A. Johnson's group characterised Tmem67−/− knockout mutant mice and used biochemical methods to further elucidate TMEM67 function. The group found that TMEM67 interacts with Wnt5a and receptor tyrosine kinase-like orphan receptor 2 (ROR2), two components of non-canonical Wnt signalling. Tmem67−/− embryos and pups manifest pulmonary hypoplasia phenotypes and, consistent with other available data, these are mediated by mutations of any component in the Wnt5a-TMEM67-ROR2 axis. Interestingly, pharmacological targeting of downstream effectors of this axis is able to rescue pulmonary abnormalities in cultured lungs from Tmem67−/− mice. These results implicate the dysregulation of the Wnt5a-TMEM67-ROR2 axis in ciliopathies and suggest that its downstream modulation can prevent pulmonary hypoplasia in these diseases. Page 527
Elucidating pulmonary hypoplasia in ciliopathies
Elucidating pulmonary hypoplasia in ciliopathies. Dis Model Mech 1 June 2015; 8 (6): e0602. doi:
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