title: V-ATPases Containing a3 Subunit Play a Direct Role in Enamel Development in Mice.
abstract: Vacuolar H+-ATPases (V-ATPases) are ubiquitous multisubunit proton pumps responsible for organellar pH maintenance. Mutations in the a3 subunit of V-ATPases cause autosomal recessive osteopetrosis, a rare disease due to impaired bone resorption. Patients with osteopetrosis also display dental anomalies, such as enamel defects; however, it is not clear whether these enamel abnormalities are a direct consequence of the a3 mutations. We investigated enamel mineralization, spatiotemporal expression of enamel matrix proteins and the a3 protein during tooth development using an osteopetrotic mouse model with a R740S point mutation in the V-ATPase a3 subunit. Histology revealed aberrations in both crown and root development, whereas SEM analysis demonstrated delayed enamel mineralization in homozygous animals. Enamel thickness and mineralization were significantly decreased in homozygous mice as determined by μCT analysis. The expression patterns of the enamel matrix proteins amelogenin, amelotin, and odontogenic ameloblast-associated protein (ODAM) suggested a delay in transition to the maturation stage in homozygous animals. Protein expression of the a3 subunit was detected in ameloblasts in all three genotypes, suggesting that a3-containing V-ATPases play a direct role in amelogenesis, and mutations in a3 delay transition from the secretory to the maturation stage, resulting in hypomineralized and hypoplastic enamel. J. Cell. Biochem. 118: 3328-3340, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Dentistry, Department of Oral Pathology, University of Toronto, Toronto, Ontario, Canada.|Faculty of Dentistry, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Johnson
authors.affiliation: Faculty of Dentistry, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada.|Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ganss
authors.affiliation: Faculty of Dentistry, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wang
authors.affiliation: Faculty of Dentistry, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Zirngibl
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Johnson
authors.affiliation: Centre for Modeling Human Disease, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Celeste
authors.initials: C
authors.lastname: Owen
authors.affiliation: Faculty of Dentistry, Department of Oral Pathology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Bradley
authors.affiliation: Faculty of Dentistry, Dental Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Irina
authors.identifier: 0000-0003-2369-3324
authors.initials: I
authors.lastname: Voronov
mesh_terms: D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology*; D003743:Dental Enamel / Q000201:enzymology* / Q000254:growth & development; D051379:Mice; D008817:Mice, Mutant Strains; D010022:Osteopetrosis / Q000201:enzymology / Q000235:genetics; D017354:Point Mutation; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D025262:Vacuolar Proton-Translocating ATPases
keywords: AMELOBLAST; ENAMEL; LYSOSOMAL pH; OSTEOCLAST; OSTEOPETROSIS; V-ATPase