Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of oral-facial-digital syndrome

• Main Authors: Elizabeth N. Schock, Ching-Fang Chang, Jaime N. Struve, Ya-Ting Chang, Julie Chang, Mary E. Delany, Samantha A. Brugmann
• Format: Article
• Language: English
• Published: The Company of Biologists 2015-08-01
• Series: Disease Models & Mechanisms
• Subjects: Primary cilia; Craniofacial; Neural crest; talpid2; Ciliopathies; Chicken; Oral-facial-digital syndrome
• Online Access: http://dmm.biologists.org/content/8/8/855
• ISSN: 1754-8411; 1754-8403

Oral-facial-digital syndrome (OFD) is a ciliopathy that is characterized by oral-facial abnormalities, including cleft lip and/or palate, broad nasal 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 Ca2+-dependent domain-containing 3 (C2CD3). Our previous work identified mutations in C2CD3 as the causal genetic lesion for the avian talpid2 mutant. Based on this common genetic etiology, we re-examined the talpid2 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 talpid2 cells. Furthermore, we found that all common phenotypes were conserved between OFD-affected individuals and avian talpid2 mutants. In light of these findings, we utilized the talpid2 model 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 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 CNCC migration and differentiation could contribute to the pathology of oral-facial defects in OFD.