{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T05:15:54Z","timestamp":1765170954121,"version":"3.46.0"},"reference-count":103,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["DE027345"],"award-info":[{"award-number":["DE027345"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"\n Introduction<\/jats:title>\n \n Inositol-requiring enzyme 1 alpha (IRE1\u03b1), encoded by endoplasmic reticulum (ER) to nucleus signaling 1 (\n Ern1<\/jats:italic>\n ) gene, is the most conserved sensor of ER stress. IRE1\u03b1-initiated signaling pathways contribute to functional maturation of secretory cells and have been implicated in various human diseases. In this study, we examined the roles of IRE1\u03b1 in odontoblast development and dentin formation in wild-type mice as well as in\n Dspp<\/jats:italic>\n \n P19L<\/jats:italic>\n <\/jats:sup>\n mutant mice, which express a pathogenic variant of dentin sialophosphoprotein (P19L-DSPP) and exhibit a dentinogenesis imperfecta (DGI)-like phenotype.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Western-blotting and stains-all staining analyses were used to assess whether secretion of mutant P19L-DSPP was impaired in dental pulp cells containing odontoblasts from\n Dspp<\/jats:italic>\n \n P19L\/P19L<\/jats:italic>\n <\/jats:sup>\n mice compared with\n Dspp<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n controls. Immunohistochemistry and reverse-transcription PCR were performed to examine changes in IRE1\u03b1 and its downstream target X-box binding protein 1 (XBP1) in P19L-DSPP mutant mice. To further investigate the roles of IRE1\u03b1 in tooth development, we generated\n 2.3 Col1-Cre;Ern1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n and compound\n 2.3 Col1-Cre;Ern1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n ;\n Dspp<\/jats:italic>\n \n P19L\/+<\/jats:italic>\n <\/jats:sup>\n mice. Structural and histological changes in mandibular molars were analyzed using plain X-ray radiography, micro-computed tomography (\u00b5CT), and histology. Additionally,\n in situ<\/jats:italic>\n hybridization, quantitative real-time PCR, and immunohistochemistry were performed to compare molecular changes among these mice and\n Ern1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n and\n Ern1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n ;\n Dspp<\/jats:italic>\n \n P19L\/+<\/jats:italic>\n <\/jats:sup>\n controls.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Western-blotting and stains-all staining analyses support that mutant P19L-DSPP protein was not efficiently secreted into dentin matrix and was accumulated within odontoblasts. Further, immunostaining signals for phosphorylated IRE1\u03b1 and total XBP1 were dramatically increased in odontoblasts and other dental pulp cells of\n Dspp<\/jats:italic>\n \n P19L\/+<\/jats:italic>\n <\/jats:sup>\n and\n Dspp<\/jats:italic>\n \n P19L\/P19L<\/jats:italic>\n <\/jats:sup>\n mice, in comparison with\n Dspp<\/jats:italic>\n \n +\/+<\/jats:italic>\n <\/jats:sup>\n mice. Consistently, there was a small increase in spliced XBP1S protein and\n Xbp1s<\/jats:italic>\n mRNA levels in P19L-DSPP mutant mice. Moreover, loss of IRE1\u03b1 function reduced dentin formation in 2.3\n Col1-Cre;Ern1<\/jats:italic>\n \n fl\/fl<\/jats:italic>\n <\/jats:sup>\n mice and exacerbated the dental defects of P19L-DSPP mutant mice. Notably, IRE1\u03b1 deficiency did not restore the\n Dspp<\/jats:italic>\n mRNA levels in the mutant mice but normalized the increased thickness of the dental pulp chamber floor dentin.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n These findings underscore the essential role of IRE1\u03b1 in odontoblast function and dentinogenesis. Moreover, they reveal a context-dependent pathogenic role of IRE1\u03b1, providing new insights into ER stress in dental tissue development and disease.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fphys.2025.1722417","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T05:12:29Z","timestamp":1765170749000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inositol-requiring enzyme 1 alpha is essential for dentinogenesis"],"prefix":"10.3389","volume":"16","author":[{"given":"Qian","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tian","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiahe","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Hollien","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Iwawaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunlin","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongbo","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1242\/dev.111.3.691","article-title":"Differential expression of type I and type III collagen genes during tooth development","volume":"111","author":"Andujar","year":"1991","journal-title":"Development"},{"key":"B2","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/1750-1172-3-31","article-title":"Hereditary dentine disorders: dentinogenesis imperfecta and dentine dysplasia","volume":"3","author":"Barron","year":"2008","journal-title":"Orphanet Journal Rare Diseases"},{"key":"B3","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1046\/j.0909-8836.1998.eos106510.x","article-title":"Dentin sialoprotein, dentin phosphoprotein, enamelysin and ameloblastin: tooth-specific molecules that are distinctively expressed during murine dental differentiation","volume":"106","author":"Begue-Kirn","year":"1998","journal-title":"Eur. 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