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Roles of Inositol-Requiring Enzyme 1 Alpha (IRE1α) in Odontogenesis
Abstract
Dentin sialophosphoprotein (DSPP) is highly expressed in odontoblasts that form dentin, and mutations in the DSPP gene are associated with dentinogenesis imperfecta (DGI)/dentin dysplasia (DD), which are the most common inherited dentin disorders. However, the molecular pathogenesis of mutant DSPP in DGI is largely unknown. As the most conserved endoplasmic reticulum (ER) stress sensor, the inositol-requiring enzyme 1α (IRE1α) pathway plays important roles in the pathophysiological processes and has profound effects on disease progression and prognosis. IRE1α deals with ER stress by unconventional splicing of x-box binding protein 1 (XBP1) mRNA, or regulated IRE1-dependent decay (RIDD).
Previously, we established a DSPP-KI (knock-in) mouse model with the P19L mutation in its DSPP gene, which resembled the features of human DGI patients. We found out that the IRE1α pathway was highly activated in the dental pulp cells of the Dspp-P19L mutant mice. The goal of this study was to determine the pathophysiological roles of IRE1α in dentin formation.
We generated and characterized the transgenic mice with Ire1α specifically deleted in the odontoblasts in the wild-type and Dspp-P19L mutant mice. Compared to wild-type control, the odontoblast-specific Ire1α conditional knock-out (cKO) mice (2.3 Col1-Cre;Ire1fl/fl) exhibited enlarged dental pulp chamber and thinner pulp chamber roof dentin. After Ire1α deletion in the odontoblasts of Dspp-P19L mutant control, the compound mutant mice (2.3 Col1-Cre;Ire1fl/fl;DsppP19L/+) displayed much larger dental pulp chamber and thinner roof dentin. A reduction in DSPP mRNA level and an increased intracellular retention of DSPP protein in the odontoblasts were also observed in 2.3 Col1-Cre;Ire1fl/fl;DsppP19L/+ mice. Odontoblast-specific inactivation of Ire1α did not rescue the reduced DSPP mRNA level in the odontoblasts of Dspp-P19L mutant mice, excluding the roles of RIDD in degrading DSPP mRNA in Dspp-P19L mutant mice.
Then we generated and characterized the transgenic mice that constitutively expressed spliced XBP1 (XBP1S) in the odontoblasts. The Twist2-Cre;Xbp1CS/+ mice displayed significantly reduced dentin formation and exhibited remarkably increased XBP1S protein expression in the dental pulps.
In summary, our results showed that: 1) IRE1α was required for normal dentin formation; 2) the IRE1α-XBP1 pathway, but not RIDD, was involved in DGI associated with mutant DSPP-P19L protein.
Citation
Xu, Qian (2022). Roles of Inositol-Requiring Enzyme 1 Alpha (IRE1α) in Odontogenesis. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /198102.