Inositol-requiring enzyme 1 alpha is essential for dentinogenesis

QIAN XU¹Tian Liang¹Jiahe Li¹Suzhen Wang¹Hua Zhang¹Julie Hollien²Takao Iwawaki³Chunlin Qin¹Yongbo Lu^1*

• ¹Texas A&M University College of Dentistry, Dallas, United States
• ²The University of Utah School of Biological Sciences, Salt Lake City, United States
• ³Kanazawa Medical University, Ishikawa, Japan

Inositol-requiring enzyme 1 alpha (IRE1α) is the most conserved sensor of endoplasmic reticulum (ER) stress. IRE1α-initiated signaling pathways contribute to the functional maturation of secretory cells and have been implicated in various human diseases. In this study, we have used a multi-pronged approach and examined the roles of IRE1α in odontoblast development and dentin formation in wild-type mice as well as in DsppP19L mutant mice, which express a pathogenic variant of dentin sialophosphoprotein (P19L-DSPP) and exhibit a dentinogenesis imperfecta (DGI)-like phenotype. We find that the immunostaining signals for phosphorylated IRE1α and total X-box binding protein 1 (XBP1) are dramatically increased in the odontoblasts and other dental pulp cells of DsppP19L/+ and DsppP19L/P19L mice, in comparison with Dspp+/+ control mice. Consistently, there is a small increase in spliced XBP1S protein and Xbp1s mRNA levels in the P19L-DSPP mutant mice. Moreover, loss of IRE1α function reduces dentin formation in wild-type mice and exacerbates the dental defects in the P19L-DSPP mutant mice. Notably, IRE1α deficiency does not restore the Dspp mRNA levels in the mutant mice but normalizes the increased thickness of the dental pulp chamber floor dentin. These findings underscore the essential role of IRE1α in odontoblast function and dentinogenesis. Moreover, they reveal a context-dependent pathogenic role of IRE1α, providing new insights into ER stress in dental tissue development and disease.