title: Role of OVCA1/DPH1 in craniofacial abnormalities of Miller-Dieker syndrome.
abstract: OVCA1/DPH1 (OVCA1) encodes a component of the diphthamide biosynthesis pathway and is located on chromosome 17p13.3. Deletions in this region are associated with Miller-Dieker syndrome (MDS). Ovca1/Dph1 (Ovca1)-null mice exhibit multiple developmental defects, including cleft palate, growth restriction and perinatal lethality, suggesting a role in the craniofacial abnormalities associated with MDS. Conditional ablation of Ovca1 in neural crest cells, but not in cranial paraxial mesoderm, also results in cleft palate and shortened lower jaw phenotypes, similar to Ovca1-null embryos. Expression of transgenic myc-tagged Ovca1 in craniofacial structures can partially rescue the cleft palate and shortened mandible of Ovca1-null embryos. Interestingly, Ovca1-null mutants are resistant to conditional expression of diphtheria toxin subunit A in both neural crest cell and paraxial mesoderm derivatives. However, OVCA1-dependent diphthamide biosynthesis is essential for neural crest cell-derived craniofacial development but that is dispensable for paraxial mesodermal-derived craniofacial structures in mammals. These findings suggest that OVCA1 deficiency in the neural crest contributes to the craniofacial abnormalities in patients with MDS. Also, our findings provide new insights into the molecular and cellular mechanisms that lead to the craniofacial defects of MDS.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences.
authors.forename: Yi-Ru
authors.initials: YR
authors.lastname: Yu
authors.affiliation: Institute of Biochemistry and Molecular Biology, and VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: You
authors.affiliation: Institute of Biochemistry and Molecular Biology, and Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Yan
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Taiwan Mouse Clinic-National Phenotyping Center, Taipei, Taiwan cmchen@ym.edu.tw.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002874:Chromosome Mapping; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics* / Q000473:pathology*; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D015870:Gene Expression; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D009432:Neural Crest / Q000196:embryology / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D051155:Wnt1 Protein / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015778:Minor Histocompatibility Antigens; D025521:Tumor Suppressor Proteins; D051155:Wnt1 Protein; C121987:DPH1 protein, human; C101538:Mesp1 protein, mouse