Dmm020222 855..866
نویسندگان
چکیده
Oral-facial-digital syndrome (OFD) is a ciliopathy that is characterized byoral-facial abnormalities, includingcleft lip and/orpalate, broadnasal root, dental anomalies, micrognathia and glossal defects. In addition, these individuals have several other characteristic abnormalities that are typical of a ciliopathy, including polysyndactyly, polycystic kidneys and hypoplasia of the cerebellum. Recently, a subset of OFD cases in humans has been linked to mutations in the centriolar protein C2 Ca-dependent domain-containing 3 (C2CD3). Our previous work identifiedmutations inC2CD3 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-affected individuals, protein-protein interactions between C2CD3 and oral-facial-digital syndrome 1 protein (OFD1) are reduced in talpid cells. Furthermore, we found that all common phenotypes were conserved between OFDaffected individuals and avian talpidmutants. In light of these findings, we utilized the talpid model to examine the cellular basis for the oralfacial phenotypes present in OFD. Specifically, we examined the development and differentiation of cranial neural crest cells (CNCCs) when C2CD3-dependent ciliogenesis was impaired. Our studies suggest that although 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 CNCCmigration and differentiation could contribute to the pathology of oral-facial defects in OFD.
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تاریخ انتشار 2015