MLL4 regulates palatal salivary gland development

Palatal glands are minor mucous salivary glands that contribute to oral lubrication and mucosal defense through the secretion of mucus and protective factors such as secretory immunoglobulin A. They are also the most common site of benign and malignant minor salivary gland tumors. Despite their physiological and clinical importance, the molecular mechanisms underlying palatal gland development remain poorly understood. Given the essential role of the epigenetic regulator MLL4 (KMT2D) in craniofacial development, we investigated its role in palatal gland development using a conditional knockout (cKO) mouse model with tissue-specific deletion of Mll4 in the palatal mesenchyme (Mll4fl/fl;Osr2-Cre). Mll4-cKO mice exhibited palatal gland hypoplasia from birth through adulthood, accompanied by ectopic cartilage formation in the soft palate. RNA-seq analysis revealed downregulation of genes and biological processes associated with salivary gland development, branching morphogenesis, and FGF and WNT signaling, together with upregulation of biological processes related to chondrocyte proliferation, consistent with the glandular hypoplasia and ectopic cartilage phenotypes. In situ hybridization and immunofluorescence analyses confirmed reduced mesenchymal Fgf10 expression, decreased epithelial SOX9 and Edar expression, and localized accumulation of SOX9-positive cells within the ectopic cartilage. Ki67 immunostaining demonstrated reduced epithelial cell proliferation without altered apoptosis in Mll4-cKO palatal glands. Collectively, these findings identify MLL4 as an essential epigenetic regulator of palatal gland morphogenesis that coordinates mesenchymal-epithelial signaling while maintaining normal developmental programs within the soft palate.