title: Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice.
abstract: Cleft palate is among the most common human birth defects. Submucous cleft palate (SMCP) is a subgroup of cleft palate, which may be as common as overt cleft palate. Despite the high frequency of SMCP in humans, only recently have several animal models of SMCP begun to provide insight into the mechanisms by which SMCP develops. In this study, we show that enhanced BMP signaling through constitutively active ACVR1 in palatal epithelium causes submucous cleft palate in mice. In these mutant mice, the fusion of both palatal mesenchyme in hard palate, and muscles in soft palate were hampered by epithelial tissue. During palatal fusion, enhanced SMAD-dependent BMP signaling impaired cell death and altered cell proliferation rate in medial edge epithelium (MEE), and resulted in MEE persistence. At the molecular level, downregulation of ΔNp63, which is crucial for normal palatal fusion, in MEE cells was impaired, leading to a reduction in caspase-3 activation. Our study provides a new insight into the etiology of SMCP caused by augmented BMP signaling.
authors.affiliation: Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Noda
authors.affiliation: Department of Biologic and Materials Science, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.affiliation: Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA. Electronic address: Yoshihiro.Komatsu@uth.tmc.edu.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komatsu
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D053148:Caspase 3 / Q000502:physiology; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation; D004848:Epithelium / Q000196:embryology* / Q000473:pathology; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008445:Maxillofacial Development / Q000502:physiology*; D008648:Mesoderm / Q000196:embryology; D051379:Mice; D009061:Mouth Mucosa / Q000196:embryology* / Q000473:pathology; D009154:Mutation; D009924:Organ Culture Techniques; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D051785:Smad Proteins / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D019485:Bone Morphogenetic Proteins; D008164:Luminescent Proteins; D010750:Phosphoproteins; D051785:Smad Proteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: BMP; Craniofacial development; Medial edge epithelium; Palatogenesis; ΔNp63