Abstract
ABSTRACTOral-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.
Highlights
To better understand the cellular etiology for the oral-facial defects in Oral-facial-digital syndrome (OFD)-affected individuals and talpid2 mutants, the authors examine a population of embryonic cells called cranial neural crest cells (CNCCs), which give rise to a large portion of the oral-facial complex that is affected in OFD
Implications and future directions These findings suggest that the oral-facial defects in individuals with OFD might be due to disruptions in CNCC migration and differentiation during development, thereby highlighting two cellular processes that might be crucial for the onset of this disease
Future work will focus on understanding the mechanism that is responsible for altered migration and differentiation in CNCCs that lack C2CD3-dependent ciliogenesis
Summary
The most well-known examples of oral-facial ciliopathies are BardetBiedl syndrome, Joubert syndrome, Meckel-Gruber syndrome and oral-facial-digital syndrome (OFD) (Beales et al, 1999; Ferrante et al, 2001; Fraser and Lytwyn, 1981; Lorda-Sanchez et al, 2001; Maria et al, 1999). For many of these syndromes, both the genetic basis and the cellular processes that are affected remain unclear
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