The Meckel-Gruber Syndrome protein TMEM67 (meckelin) regulates basal body planar polarization and non-canonical Wnt signalling via Wnt5a and ROR2

Results: Tmem67 mutant phenotypes 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. TMEM67 (meckelin) is essential for phosphorylation of the noncanonical Wnt receptor ROR2 (receptor tyrosine kinaselike orphan receptor 2) upon Wnt5a stimulation. ROR2 interacts with the intracellular C-terminal domain of TMEM67 and co-localizes with TMEM67 at the ciliary transition zone. The N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Tmem67 mutant embryonic lungs in ex vivo culture failed to respond to Wnt5a stimulation of epithelial morphogenesis. However, stimulating the non-canonical Wnt pathway downstream of the receptor by activating RhoA resulted in an elicited response and the rescue of lung hypoplasia phenotypes.