Store-operated Ca 2+ entry controls ameloblast cell function and enamel development

Miriam Eckstein, Martin Vaeth, Cinzia Fornai, Manikandan Vinu, Timothy Bromage, Meerim K. Nurbaeva, Jessica L. Sorge, Paulo Coelho, Youssef Idaghdhour, Stefan Feske, Rodrigo Lacruz

Research output: Contribution to journalArticle

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 generated Stim1/2K14cre mice to delete STIM1 and its homolog STIM2 in enamel cells. These mice showed impaired SOCE in enamel cells. Enamel in Stim1/2K14cre mice 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 in Stim1/2-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 of Stim1/2K14cre mice. 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.

Original languageEnglish (US)
Pages (from-to)e91166
JournalJCI insight
Volume2
Issue number6
DOIs
StatePublished - Mar 23 2017

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Ameloblasts
Dental Enamel
Channelopathies
Unfolded Protein Response
Gene Expression
Glutathione
Mitochondria
Oxidative Stress
Animal Models
Mutation

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Store-operated Ca 2+ entry controls ameloblast cell function and enamel development . / Eckstein, Miriam; Vaeth, Martin; Fornai, Cinzia; Vinu, Manikandan; Bromage, Timothy; Nurbaeva, Meerim K.; Sorge, Jessica L.; Coelho, Paulo; Idaghdhour, Youssef; Feske, Stefan; Lacruz, Rodrigo.

In: JCI insight, Vol. 2, No. 6, 23.03.2017, p. e91166.

Research output: Contribution to journalArticle

Eckstein, Miriam ; Vaeth, Martin ; Fornai, Cinzia ; Vinu, Manikandan ; Bromage, Timothy ; Nurbaeva, Meerim K. ; Sorge, Jessica L. ; Coelho, Paulo ; Idaghdhour, Youssef ; Feske, Stefan ; Lacruz, Rodrigo. / Store-operated Ca 2+ entry controls ameloblast cell function and enamel development In: JCI insight. 2017 ; Vol. 2, No. 6. pp. e91166.
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