Using the avian mutant talpid as a disease model for understanding the oral- facial phenotypes of Oral-facial-digital syndrome

Oral-facial-digital syndrome (OFD) is a ciliopathy characterized by oral-facial abnormalities including cleft lip/palate, broad nasal root, dental anomalies, micrognathia and glossal defects. In addition, these patients have several other characteristic abnormalities typical of a ciliopathy including polysyndactyly, polycystic kidneys and hypoplasia of the cerebellum. Recently, a subset of human OFD cases has been linked to mutations in the centriolar protein C2 calciumdependent domain-containing 3 (C2CD3). Our previous work identified mutations in C2CD3 as the causal genetic lesion for the avian talpid mutant. Based on this common genetic etiology, we re-examined the talpid mutant biochemically and phenotypically for characteristics of OFD. We found that, as in OFD patients, proteinprotein interactions between C2CD3 and OFD1 are reduced in talpid cells. Furthermore, we found that all common phenotypes were conserved between human OFD patients and avian talpid mutants. In light of these findings, we utilized the talpid to examine the cellular basis for the oral-facial phenotypes present in OFD. Specifically, we examined the development and differentiation of cranial neural crest cells (CNCCs) when C2CD3-dependent ciliogenesis is impaired. Our studies suggest that, whereas disruptions of C2CD3-dependent ciliogenesis do not affect CNCC specification or proliferation, CNCC migration and differentiation are disrupted. Loss of C2CD3-dependent ciliogenesis affects the dispersion and directional persistence of migratory CNCCs. Furthermore, loss of C2CD3-dependent ciliogenesis results in dysmorphic and enlarged CNCC-derived facial cartilages. Thus, these findings suggest that aberrant CNCC migration and differentiation could contribute to the pathology of oral-facial defects in OFD. D ise as e M od el s & M ec ha ni sm s D M M Ac ce pt ed m an us cr ip t