title: Loss of Function of Evc2 in Dental Mesenchyme Leads to Hypomorphic Enamel.
abstract: Ellis-van Creveld (EvC) syndrome is an autosomal-recessive skeletal dysplasia, characterized by short stature and postaxial polydactyly. A series of dental abnormalities, including hypomorphic enamel formation, has been reported in patients with EvC. Despite previous studies that attempted to uncover the mechanism leading to abnormal tooth development, little is known regarding how hypomorphic enamel is formed in patients with EvC. In the current study, using Evc2/ Limbin mutant mice we recently generated, we analyzed enamel formation in the mouse incisor. Consistent with symptoms in human patients, we observed that Evc2 mutant mice had smaller incisors with enamel hypoplasia. Histologic observations coupled with ameloblast marker analyses suggested that Evc2 mutant preameloblasts were capable of differentiating to secretory ameloblasts; this process, however, was apparently delayed, due to delayed odontoblast differentiation, mediated by a limited number of dental mesenchymal stem cells in Evc2 mutant mice. This concept was further supported by the observation that dental mesenchymal-specific deletion of Evc2 phenocopied the tooth abnormalities in Evc2 mutants. Overall, our findings suggest that mutations in Evc2 affect dental mesenchymal stem cell homeostasis, which further leads to hypomorphic enamel formation.
authors.affiliation: 1 Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 2 Unit of Animal Genomics, GIGA Research Center and Faculty of Veterinary Medicine, University of Liège, 1 Avenue de l'Hôpital, Liège, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Takeda
authors.affiliation: 3 Graduate School of Environmental and Life Science, Okayama University, Okayama City, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: 1 Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.|Faculty of Budo and Sport Studies, Tenri University, Nara, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kamiya
authors.affiliation: 3 Graduate School of Environmental and Life Science, Okayama University, Okayama City, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kunieda
authors.affiliation: 4 Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Mochida
authors.affiliation: 1 Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Mishina
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003744:Dental Enamel Hypoplasia / Q000235:genetics*; D004195:Disease Models, Animal; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics; D007180:Incisor / Q000002:abnormalities*; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D014071:Tooth Abnormalities / Q000235:genetics*
chemical_list: C541939:EVC2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins
keywords: Hedgehog signaling; Limbin; ameloblast; cilium; odontoblast; stem cells