title: Store-operated Ca2+entry controls ameloblast cell function and enamel development.
abstract: Loss-of-function mutations in stromal interaction molecule 1 (STIM1) impair the activation of Ca2+release-activated Ca2+(CRAC) channels and store-operated Ca2+entry (SOCE), resulting in a disease syndrome called CRAC channelopathy that is characterized by severe dental enamel defects. The cause of these enamel defects has remained unclear given a lack of animal models. We generatedStim1/2K14cremice to delete STIM1 and its homolog STIM2 in enamel cells. These mice showed impaired SOCE in enamel cells. Enamel inStim1/2K14cremice was hypomineralized with decreased Ca content, mechanically weak, and thinner. The morphology of SOCE-deficient ameloblasts was altered, showing loss of the typical ruffled border, resulting in mislocalized mitochondria. Global gene expression analysis of SOCE-deficient ameloblasts revealed strong dysregulation of several pathways. ER stress genes associated with the unfolded protein response were increased inStim1/2-deficient cells, whereas the expression of components of the glutathione system were decreased. Consistent with increased oxidative stress, we found increased ROS production, decreased mitochondrial function, and abnormal mitochondrial morphology in ameloblasts ofStim1/2K14cremice. Collectively, these data show that loss of SOCE in enamel cells has substantial detrimental effects on gene expression, cell function, and the mineralization of dental enamel.
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Eckstein
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Vaeth
authors.affiliation: Department of Anthropology, University of Vienna, Vienna, Austria.|Department of Evolutionary Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Fornai
authors.affiliation: Biology Program, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Vinu
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA.|Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, New York, USA.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Bromage
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA.
authors.forename: Meerim K
authors.initials: MK
authors.lastname: Nurbaeva
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Sorge
authors.affiliation: Department of Biomaterials and Biomimetics, New York University College of Dentistry, New York, New York, USA.
authors.forename: Paulo G
authors.initials: PG
authors.lastname: Coelho
authors.affiliation: Biology Program, Division of Science and Mathematics, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Idaghdour
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
authors.affiliation: Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York, USA.
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Lacruz
mesh_terms: D000565:Ameloblasts / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003743:Dental Enamel / Q000254:growth & development* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D007473:Ion Channels / Q000378:metabolism*; D017136:Ion Transport; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics / Q000378:metabolism*; D000071738:Stromal Interaction Molecule 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D017382:Reactive Oxygen Species; C100757:Stim1 protein, mouse; C525024:Stim2 protein, mouse; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D002118:Calcium