title: Using the avian mutant talpid2 as a disease model for understanding the oral-facial phenotypes of oral-facial-digital syndrome.
abstract: 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 Ca(2+)-dependent domain-containing 3 (C2CD3). Our previous work identified mutations in C2CD3 as the causal genetic lesion for the avian talpid(2) mutant. Based on this common genetic etiology, we re-examined the talpid(2) 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(2) cells. Furthermore, we found that all common phenotypes were conserved between OFD-affected individuals and avian talpid(2) mutants. In light of these findings, we utilized the talpid(2) 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.
authors.affiliation: Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Schock
authors.affiliation: Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ching-Fang
authors.initials: CF
authors.lastname: Chang
authors.affiliation: Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jaime N
authors.initials: JN
authors.lastname: Struve
authors.affiliation: Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Chang
authors.affiliation: College of Agricultural and Environmental Sciences, Department of Animal Science, University of California Davis, Davis, CA 95616, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Delany
authors.affiliation: Division of Plastic Surgery, Department of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA samantha.brugmann@cchmc.org.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Brugmann
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002642:Chick Embryo; D002645:Chickens; D002923:Cilia / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009432:Neural Crest / Q000196:embryology / Q000473:pathology; D038081:Organogenesis; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype
chemical_list: D030161:Avian Proteins; D018797:Cell Cycle Proteins
keywords: Chicken; Ciliopathies; Craniofacial; Neural crest; Oral-facial-digital syndrome; Primary cilia; talpid2