Inositol-requiring enzyme 1 alpha is essential for dentinogenesis

Area of Science:

• Molecular Biology
• Cell Biology
• Developmental Biology

Background:

• Inositol-requiring enzyme 1 alpha (IRE1α) is a key sensor of endoplasmic reticulum (ER) stress, vital for secretory cell maturation and implicated in human diseases.
• Odontoblasts are critical for dentin formation, and their dysfunction leads to dental defects like dentinogenesis imperfecta (DGI).

Purpose of the Study:

• To investigate the role of IRE1α in odontoblast development and dentin formation.
• To analyze the impact of IRE1α deficiency on dentinogenesis in the context of a pathogenic dentin sialophosphoprotein (DSPP) variant.

Main Methods:

• Utilized Western-blotting, stains-all staining, immunohistochemistry, and RT-PCR to assess protein secretion and IRE1α/XBP1 pathway activation in wild-type and mutant mice.
• Generated genetically modified mice (2.3 Col1-Cre;Ern1^fl/fl and compound mutants) to study IRE1α function in tooth development.
• Analyzed structural and histological changes in mandibular molars using radiography, micro-CT, and histology.

Main Results:

• Mutant P19L-DSPP protein accumulated within odontoblasts, indicating impaired secretion.
• IRE1α and XBP1 pathway activation (increased p-IRE1α, total XBP1, spliced XBP1S) was observed in odontoblasts of DSPP mutant mice.
• Loss of IRE1α function reduced dentin formation and exacerbated dental defects in DSPP mutant mice, while normalizing pulp chamber dentin thickness.

Conclusions:

• IRE1α plays an essential role in odontoblast function and dentinogenesis.
• The study reveals a context-dependent pathogenic role for IRE1α in dental tissue development and disease, highlighting the significance of ER stress pathways.