Synergistic Role of Retinoid and Gata3 Signaling in Olfactory Epithelium Development

Craniofacial development requires precise coordination of epithelial patterning and morphogenesis. However, the molecular mechanisms governing olfactory epithelium development remain incompletely understood. Retinoic acid (RA) signaling and Gata3 have each been independently implicated in craniofacial morphogenesis, particularly in the formation of the primitive choanae, which constitute the opening between the nasal cavity and the oral cavity. Here, we generated a tamoxifen-inducible, genetically controlled compound mutant mouse model to simultaneously disrupt Rdh10, a rate-limiting enzyme for RA signaling, and Gata3 during early craniofacial development. We show that while deletion of Rdh10 following tamoxifen administration at E8.5 does not result in obvious craniofacial abnormalities, combined loss of Rdh10 and Gata3 leads to fully penetrant bilateral choanal atresia and severe defects in olfactory epithelium morphogenesis. Immunohistochemical analyses revealed a marked reduction in PAX6 and SIX1 positive cells and a concomitant expansion of SOX2 positive cells in compound mutant embryos. These results demonstrate that RA-Gata3 signaling cooperatively regulates olfactory epithelium development by controlling the balance between progenitor maintenance and lineage specification. We propose that the RA-Gata3 signaling pathway orchestrates a transcriptional network involving Pax6, Six1, and Sox2 to ensure proper epithelial patterning, branching morphogenesis, and choanae formation during early craniofacial development.