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STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone

Gamage, Thilini H; Lengle, Emma; Gunnes, Gjermund; Pullisaar, Helen; Holmgren, Asbjørn; Reseland, Janne E; Merckoll, Else; Corti, Stefania; Mizobuchi, Masahiro; Morales, Raul J; Tsiokas, Leonidas; Tjønnfjord, Geir E; Lacruz, Rodrigo S; Lyngstadaas, Staale P; Misceo, Doriana; Frengen, Eirik
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.
PMID: 31785581
ISSN: 1532-1991
CID: 4216492

The evolutionary history of the human face

Lacruz, Rodrigo S; Stringer, Chris B; Kimbel, William H; Wood, Bernard; Harvati, Katerina; O'Higgins, Paul; Bromage, Timothy G; Arsuaga, Juan-Luis
The face is the most distinctive feature used to identify others. Modern humans have a short, retracted face beneath a large globular braincase that is distinctively different from that of our closest living relatives. The face is a skeletal complex formed by 14 individual bones that houses parts of the digestive, respiratory, visual and olfactory systems. A key to understanding the origin and evolution of the human face is analysis of the faces of extinct taxa in the hominin clade over the last 6 million years. Yet, as new fossils are recovered and the number of hominin species grows, the question of how and when the modern human face originated remains unclear. By examining key features of the facial skeleton, here we evaluate the evolutionary history of the modern human face in the context of its development, morphology and function, and suggest that its appearance is the result of a combination of biomechanical, physiological and social influences.
PMID: 30988489
ISSN: 2397-334x
CID: 3810792

Differential regulation of Ca2+ influx by ORAI channels mediates enamel mineralization

Eckstein, Miriam; Vaeth, Martin; Aulestia, Francisco J; Costiniti, Veronica; Kassam, Serena N; Bromage, Timothy G; Pedersen, Pal; Issekutz, Thomas; Idaghdour, Youssef; Moursi, Amr M; Feske, Stefan; Lacruz, Rodrigo S
Store-operated Ca2+ entry (SOCE) channels are highly selective Ca2+ channels activated by the endoplasmic reticulum (ER) sensors STIM1 and STIM2. Their direct interaction with the pore-forming plasma membrane ORAI proteins (ORAI1, ORAI2, and ORAI3) leads to sustained Ca2+ fluxes that are critical for many cellular functions. Mutations in the human ORAI1 gene result in immunodeficiency, anhidrotic ectodermal dysplasia, and enamel defects. In our investigation of the role of ORAI proteins in enamel, we identified enamel defects in a patient with an ORAI1 null mutation. Targeted deletion of the Orai1 gene in mice showed enamel defects and reduced SOCE in isolated enamel cells. However, Orai2-/- mice showed normal enamel despite having increased SOCE in the enamel cells. Knockdown experiments in the enamel cell line LS8 suggested that ORAI2 and ORAI3 modulated ORAI1 function, with ORAI1 and ORAI2 being the main contributors to SOCE. ORAI1-deficient LS8 cells showed altered mitochondrial respiration with increased oxygen consumption rate and ATP, which was associated with altered redox status and enhanced ER Ca2+ uptake, likely due to S-glutathionylation of SERCA pumps. Our findings demonstrate an important role of ORAI1 in Ca2+ influx in enamel cells and establish a link between SOCE, mitochondrial function, and redox homeostasis.
PMID: 31015290
ISSN: 1937-9145
CID: 3821202

Tissue resident and follicular Treg cell differentiation is regulated by CRAC channels

Vaeth, Martin; Wang, Yin-Hu; Eckstein, Miriam; Yang, Jun; Silverman, Gregg J; Lacruz, Rodrigo S; Kannan, Kasthuri; Feske, Stefan
T regulatory (Treg) cells maintain immunological tolerance and organ homeostasis. Activated Treg cells differentiate into effector Treg subsets that acquire tissue-specific functions. Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels formed by STIM and ORAI proteins is required for the thymic development of Treg cells, but its function in mature Treg cells remains unclear. Here we show that deletion of Stim1 and Stim2 genes in mature Treg cells abolishes Ca2+ signaling and prevents their differentiation into follicular Treg and tissue-resident Treg cells. Transcriptional profiling of STIM1/STIM2-deficient Treg cells reveals that Ca2+ signaling regulates transcription factors and signaling pathways that control the identity and effector differentiation of Treg cells. In the absence of STIM1/STIM2 in Treg cells, mice develop a broad spectrum of autoantibodies and fatal multiorgan inflammation. Our findings establish a critical role of CRAC channels in controlling lineage identity and effector functions of Treg cells.
PMID: 30862784
ISSN: 2041-1723
CID: 3732832

CRAC channels in dental enamel cells

Eckstein, M; Lacruz, R S
Enamel mineralization relies on Ca2+ availability provided by Ca2+ release activated Ca2+ (CRAC) channels. CRAC channels are modulated by the endoplasmic reticulum Ca2+ sensor STIM1 which gates the pore subunit of the channel known as ORAI1, found the in plasma membrane, to enable sustained Ca2+ influx. Mutations in the STIM1 and ORAI1 genes result in CRAC channelopathy, an ensemble of diseases including immunodeficiency, muscular hypotonia, ectodermal dysplasia with defects in sweat gland function and abnormal enamel mineralization similar to amelogenesis imperfecta (AI). In some reports, the chief medical complain has been the patient's dental health, highlighting the direct and important link between CRAC channels and enamel. The reported enamel defects are apparent in both the deciduous and in permanent teeth and often require extensive dental treatment to provide the patient with a functional dentition. Among the dental phenotypes observed in the patients, discoloration, increased wear, hypoplasias (thinning of enamel) and chipping has been reported. These findings are not universal in all patients. Here we review the mutations in STIM1 and ORAI1 causing AI-like phenotype, and evaluate the enamel defects in CRAC channel deficient mice. We also provide a brief overview of the role of CRAC channels in other mineralizing systems such as dentine and bone.
PMID: 30114531
ISSN: 1532-1991
CID: 3241162

Altered Ca2+ signaling in enamelopathies

Eckstein, Miriam; Aulestia, Francisco J; Nurbaeva, Meerim K; Lacruz, Rodrigo S
Biomineralization requires the controlled movement of ions across cell barriers to reach the sites of crystal growth. Mineral precipitation occurs in aqueous phases as fluids become supersaturated with specific ionic compositions. In the biological world, biomineralization is dominated by the presence of calcium (Ca2+) in crystal lattices. Ca2+ channels are intrinsic modulators of this process, facilitating the availability of Ca2+ within cells in a tightly regulated manner in time and space. Unequivocally, the most mineralized tissue produced by vertebrates, past and present, is dental enamel. With some of the longest carbonated hydroxyapatite (Hap) crystals known, dental enamel formation is fully coordinated by specialized epithelial cells of ectodermal origin known as ameloblasts. These cells form enamel in two main developmental stages: a) secretory; and b) maturation. The secretory stage is marked by volumetric growth of the tissue with limited mineralization, and the opposite is found in the maturation stage, as enamel crystals expand in width concomitant with increased ion transport. Disruptions in the formation and/or mineralization stages result, in most cases, in permanent alterations in the crystal assembly. This introduces weaknesses in the material properties affecting enamel's hardness and durability, thus limiting its efficacy as a biting, chewing tool and increasing the possibility of pathology. Here, we briefly review enamel development and discuss key properties of ameloblasts and their Ca2+-handling machinery, and how alterations in this toolkit result in enamelopathies.
PMID: 29750989
ISSN: 0006-3002
CID: 3101742

Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of Cutaneous T Cell Lymphoma

Fanok, Melania H; Sun, Amy; Fogli, Laura K; Narendran, Vijay; Eckstein, Miriam; Kannan, Kasthuri; Dolgalev, Igor; Lazaris, Charalampos; Heguy, Adriana; Laird, Mary E; Sundrud, Mark S; Liu, Cynthia; Kutok, Jeff; Lacruz, Rodrigo S; Latkowski, Jo-Ann; Aifantis, Iannis; Odum, Niels; Hymes, Kenneth B; Goel, Swati; Koralov, Sergei B
Cutaneous T cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome revealed a highly heterogeneous landscape of genetic perturbations and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway, previously implicated in CTCL pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of CTCL. Using this mouse model, we demonstrate that T cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.
PMCID:5912980
PMID: 29128259
ISSN: 1523-1747
CID: 2785082

The biting performance of Homo sapiens and Homo heidelbergensis

Godinho, Ricardo Miguel; Fitton, Laura C; Toro-Ibacache, Viviana; Stringer, Chris B; Lacruz, Rodrigo S; Bromage, Timothy G; O'Higgins, Paul
Modern humans have smaller faces relative to Middle and Late Pleistocene members of the genus Homo. While facial reduction and differences in shape have been shown to increase biting efficiency in Homo sapiens relative to these hominins, facial size reduction has also been said to decrease our ability to resist masticatory loads. This study compares crania of Homo heidelbergensis and H. sapiens with respect to mechanical advantages of masticatory muscles, force production efficiency, strains experienced by the cranium and modes of deformation during simulated biting. Analyses utilize X-ray computed tomography (CT) scan-based 3D models of a recent modern human and two H. heidelbergensis. While having muscles of similar cross-sectional area to H. heidelbergensis, our results confirm that the modern human masticatory system is more efficient at converting muscle forces into bite forces. Thus, it can produce higher bite forces than Broken Hill for equal muscle input forces. This difference is the result of alterations in relative in and out-lever arm lengths associated with well-known differences in midfacial prognathism. Apparently at odds with this increased efficiency is the finding that the modern human cranium deforms more, resulting in greater strain magnitudes than Broken Hill when biting at the equivalent tooth. Hence, the facial reduction that characterizes modern humans may not have evolved as a result of selection for force production efficiency. These findings provide further evidence for a degree of uncoupling between form and function in the masticatory system of modern humans. This may reflect the impact of food preparation technologies. These data also support previous suggestions that differences in bite force production efficiency can be considered a spandrel, primarily driven by the midfacial reduction in H. sapiens that occurred for other reasons. Midfacial reduction plausibly resulted in a number of other significant changes in morphology, such as the development of a chin, which has itself been the subject of debate as to whether or not it represents a mechanical adaptation or a spandrel.
PMID: 29606203
ISSN: 1095-8606
CID: 3025422

Evidence That Calcium Entry Into Calcium-Transporting Dental Enamel Cells Is Regulated by Cholecystokinin, Acetylcholine and ATP

Nurbaeva, Meerim K; Eckstein, Miriam; Devotta, Arun; Saint-Jeannet, Jean-Pierre; Yule, David I; Hubbard, Michael J; Lacruz, Rodrigo S
Dental enamel is formed by specialized epithelial cells which handle large quantities of Ca2+ while producing the most highly mineralized tissue. However, the mechanisms used by enamel cells to handle bulk Ca2+ safely remain unclear. Our previous work contradicted the dogma that Ca2+ is ferried through the cytosol of Ca2+-transporting cells and instead suggested an organelle-based route across enamel cells. This new paradigm involves endoplasmic reticulum (ER)-associated Ca2+ stores and their concomitant refilling by store-operated Ca2+ entry (SOCE) mediated by Ca2+ release activated Ca2+ (CRAC) channels. Given that Ca2+ handling is maximal during the enamel-mineralization stage (maturation), we anticipated that SOCE would also be elevated then. Confirmation was obtained here using single-cell recordings of cytosolic Ca2+ concentration ([Ca2+]cyt) in rat ameloblasts. A candidate SOCE agonist, cholecystokinin (CCK), was found to be upregulated during maturation, with Cck transcript abundance reaching 30% of that in brain. CCK-receptor transcripts were also detected and Ca2+ imaging showed that CCK stimulation increased [Ca2+]cyt in a dose-responsive manner that was sensitive to CRAC-channel inhibitors. Similar effects were observed with two other SOCE activators, acetylcholine and ATP, whose receptors were also found in enamel cells. These results provide the first evidence of a potential regulatory system for SOCE in enamel cells and so strengthen the Ca2+ transcytosis paradigm for ER-based transport of bulk Ca2+. Our findings also implicate enamel cells as a new physiological target of CCK and raise the possibility of an auto/paracrine system for regulating Ca2+ transport.
PMCID:6036146
PMID: 30013487
ISSN: 1664-042x
CID: 3200582

Meeting report: a hard look at the state of enamel research

Klein, Ophir D; Duverger, Olivier; Shaw, Wendy; Lacruz, Rodrigo S; Joester, Derk; Moradian-Oldak, Janet; Pugach, Megan K; Wright, J Timothy; Millar, Sarah E; Kulkarni, Ashok B; Bartlett, John D; Diekwisch, Thomas Gh; DenBesten, Pamela; Simmer, James P
The Encouraging Novel Amelogenesis Models and Ex vivo cell Lines (ENAMEL) Development workshop was held on 23 June 2017 at the Bethesda headquarters of the National Institute of Dental and Craniofacial Research (NIDCR). Discussion topics included model organisms, stem cells/cell lines, and tissues/3D cell culture/organoids. Scientists from a number of disciplines, representing institutions from across the United States, gathered to discuss advances in our understanding of enamel, as well as future directions for the field.
PMCID:5775332
PMID: 29165423
ISSN: 2049-3169
CID: 2791432