Elucidating pulmonary hypoplasia in ciliopathies

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