talpid²: a mystery finally solved

The chicken talpid² and talpid³ mutants display a range of developmental phenotypes including craniofacial and limb defects. Although links to the sonic hedgehog (SHH) pathway had been proposed, the molecular nature of these mutations remained unclear for many years. The talpid³ phenotype is known to be caused by mutation in a ciliary protein – consistent with the known function of the cilium in SHH signal transduction. Now (p. 3003), Samantha Brugmann and colleagues turn their attention to talpid². Focusing on the craniofacial phenotype, they show that talpid² mutants display loss of coupling between ligand expression levels and SHH pathway activity as well as increased levels of GLI3A – the activator form of one of the transcription factors that mediate SHH signalling. At a cellular level, cilia fail to form properly in the mutants. Using whole genome sequencing approaches, the authors identify lesions in the ciliary protein C2CD3 in talpid² mutants. Identification of the talpid² locus has been long awaited, and although there is still much to understand about how C2CD3 regulates cilia formation and function, and SHH signalling, these data provide an important step in this direction.