AUTHOR=Said Raed , Lobanova Liubov , Papagerakis Silvana , Papagerakis Petros 

TITLE=Calcium Sets the Clock in Ameloblasts

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00920

DOI=10.3389/fphys.2020.00920

ISSN=1664-042X

ABSTRACT=<sec><title>Background</title><p>Stromal interaction molecule 1 (<italic>STIM1</italic>) is one of the main components of the store operated Ca<sup>2+</sup> entry (SOCE) signaling pathway. Individuals with mutated <italic>STIM1</italic> present severely hypomineralized enamel characterized as amelogenesis imperfecta (AI) but the downstream molecular mechanisms involved remain unclear. Circadian clock signaling plays a key role in regulating the enamel thickness and mineralization, but the effects of <italic>STIM1</italic>-mediated AI on circadian clock are unknown.</p></sec><sec><title>Objectives</title><p>The aim of this study is to examine the potential links between SOCE and the circadian clock during amelogenesis.</p></sec><sec><title>Methods</title><p>We have generated mice with ameloblast-specific deletion of <italic>Stim1</italic> (<italic>Stim1</italic><sup>fl/fl</sup>/Amelx-iCre<sup>+/+</sup>, <italic>Stim1</italic> cKO) and analyzed circadian gene expression profile in <italic>Stim1 cKO</italic> compared to control (<italic>Stim1</italic><sup>fl/fl</sup>/Amelx-iCre<sup>–/–</sup>) using ameloblast micro-dissection and RNA micro-array of 84 circadian genes. Expression level changes were validated by qRT-PCR and immunohistochemistry.</p></sec><sec><title>Results</title><p><italic>Stim1</italic> deletion has resulted in significant upregulation of the core circadian activator gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocation 1 (<italic>Bmal1</italic>) and downregulation of the circadian inhibitor Period 2 (<italic>Per2</italic>). Our analyses also revealed that SOCE disruption results in dysregulation of two additional circadian regulators; p38α mitogen-activated protein kinase (MAPK14) and transforming growth factor-beta1 (TGF-β1). Both MAPK14 and TGF-β1 pathways are known to play major roles in enamel secretion and their dysregulation has been previously implicated in the development of AI phenotype.</p></sec><sec><title>Conclusion</title><p>These data indicate that disruption of SOCE significantly affects the ameloblasts molecular circadian clock, suggesting that alteration of the circadian clock may be partly involved in the development of <italic>STIM1</italic>-mediated AI.</p></sec>