STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone.,Cell Calcium

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STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone.
Cell Calcium ( IF 4.3 ) Pub Date : 2019-11-13 , DOI: 10.1016/j.ceca.2019.102110
Thilini H Gamage ₁ , Emma Lengle ₁ , Gjermund Gunnes ₂ , Helen Pullisaar ₃ , Asbjørn Holmgren ₁ , Janne E Reseland ₄ , Else Merckoll ₅ , Stefania Corti ₆ , Masahiro Mizobuchi ₇ , Raul J Morales ₈ , Leonidas Tsiokas ₉ , Geir E Tjønnfjord ₁₀ , Rodrigo S Lacruz ₁₁ , Staale P Lyngstadaas ₄ , Doriana Misceo ₁ , Eirik Frengen ₁

Affiliation

Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Norway.
Department of Orthodontics, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway.
Department of Biomaterials, Institute of Clinical Dentistry, University of Oslo, Oslo, Norway.
Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
Neurology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Neuroscience Section, Department of Pathophysiology and Transplantation, Dino Ferrari Centre, University of Milan, Milan, Italy.
Department of Neurology, Nakamura Memorial Hospital, Sapporo, Japan.
CHRU, Hôpital Gui de Chauliac, Montpellier, France.
Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma, USA.
Department of Haematology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, USA.

Calcium signaling plays a central role in bone development and homeostasis. Store operated calcium entry (SOCE) is an important calcium influx pathway mediated by calcium release activated calcium (CRAC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum calcium sensing protein important for SOCE. We generated a mouse model expressing the STIM1 R304W mutation, causing Stormorken syndrome in humans. Stim1R304W/R304W mice showed perinatal lethality, and the only three animals that survived into adulthood presented with reduced growth, low body weight, and thoracic kyphosis. Radiographs revealed a reduced number of ribs in the Stim1R304W/R304W mice. Microcomputed tomography data revealed decreased cortical bone thickness and increased trabecular bone volume fraction in Stim1R304W/R304W mice, which had thinner and more compact bone compared to wild type mice. The Stim1R304W/+ mice showed an intermediate phenotype. Histological analyses showed that the Stim1R304W/R304W mice had abnormal bone architecture, with markedly increased number of trabeculae and reduced bone marrow cavity. Homozygous mice showed STIM1 positive osteocytes and osteoblasts. These findings highlight the critical role of the gain-of-function (GoF) STIM1 R304W protein in skeletal development and homeostasis in mice. Furthermore, the novel feature of bilateral subgingival hair growth on the lower incisors in the Stim1R304W/R304W mice and 25 % of the heterozygous mice indicate that the GoF STIM1 R304W protein also induces an abnormal epithelial cell fate.

中文翻译：

小鼠中的STIM1 R304W引起龈下毛发生长和小梁骨比例增加。

钙信号传导在骨骼发育和体内平衡中起着核心作用。储库操作的钙进入（SOCE）是由质膜中钙释放活化钙（CRAC）通道介导的重要钙内流途径。基质间相互作用分子1（STIM1）是一种内质网钙敏感蛋白，对SOCE很重要。我们生成了一个小鼠模型，该模型表达STIM1 R304W突变，从而在人类中引起Stormorken综合征。Stim1R304W / R304W小鼠表现出围产期致死性，只有三只存活到成年的动物表现出生长减少，体重低和胸椎后凸畸形。射线照片显示Stim1R304W / R304W小鼠的肋骨数量减少。显微计算机断层扫描数据显示，Stim1R304W / R304W小鼠的皮质骨厚度减少，小梁骨体积分数增加，与野生型小鼠相比，它的骨骼更薄，更致密。Stim1R304W / +小鼠表现出中间表型。组织学分析表明，Stim1R304W / R304W小鼠的骨骼结构异常，小梁数量明显增加，骨髓腔减少。纯合子小鼠显示STIM1阳性骨细胞和成骨细胞。这些发现凸显了功能获得（GoF）STIM1 R304W蛋白在小鼠骨骼发育和体内稳态中的关键作用。此外，Stim1R304W / R304W小鼠和25％的杂合小鼠的下门牙双侧龈下毛发生长的新特征表明，GoF STIM1 R304W蛋白还诱导了异常的上皮细胞命运。组织学分析表明，Stim1R304W / R304W小鼠的骨骼结构异常，小梁数量明显增加，骨髓腔减少。纯合子小鼠显示STIM1阳性骨细胞和成骨细胞。这些发现凸显了功能获得（GoF）STIM1 R304W蛋白在小鼠骨骼发育和体内稳态中的关键作用。此外，在Stim1R304W / R304W小鼠和25％的杂合小鼠中，下颌切牙的双侧龈下毛发生长的新特征表明，GoF STIM1 R304W蛋白还诱导了异常的上皮细胞命运。组织学分析表明，Stim1R304W / R304W小鼠的骨骼结构异常，小梁数量明显增加，骨髓腔减少。纯合子小鼠显示STIM1阳性骨细胞和成骨细胞。这些发现凸显了功能获得（GoF）STIM1 R304W蛋白在小鼠骨骼发育和体内稳态中的关键作用。此外，在Stim1R304W / R304W小鼠和25％的杂合小鼠中，下颌切牙的双侧龈下毛发生长的新特征表明GoF STIM1 R304W蛋白也诱导了异常的上皮细胞命运。这些发现凸显了功能获得（GoF）STIM1 R304W蛋白在小鼠骨骼发育和体内稳态中的关键作用。此外，Stim1R304W / R304W小鼠和25％的杂合小鼠的下门牙双侧龈下毛发生长的新特征表明，GoF STIM1 R304W蛋白还诱导了异常的上皮细胞命运。这些发现凸显了功能获得（GoF）STIM1 R304W蛋白在小鼠骨骼发育和体内稳态中的关键作用。此外，Stim1R304W / R304W小鼠和25％的杂合小鼠的下门牙双侧龈下毛发生长的新特征表明，GoF STIM1 R304W蛋白还诱导了异常的上皮细胞命运。

更新日期：2019-11-13

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