MLL4 regulates postnatal palate growth and midpalatal suture development

Area of Science:

• Epigenetics and Developmental Biology
• Craniofacial Development
• Molecular Mechanisms of Organogenesis

Background:

• MLL4 (KMT2D) is an epigenetic regulator vital for organogenesis.
• MLL4 mutations cause Kabuki syndrome, characterized by craniofacial defects including palatal anomalies.
• The precise role of MLL4 in palate development remains to be fully elucidated.

Purpose of the Study:

• To investigate the function of MLL4 in palate development and growth.
• To uncover the molecular mechanisms underlying MLL4's role in palatal mesenchyme.
• To analyze the impact of MLL4 deletion on midpalatal suture development.

Main Methods:

• Generation of a conditional knockout (cKO) mouse model with MLL4 deletion in palatal mesenchyme.
• Micro-computed tomography (CT) for skeletal analysis.
• Histological analysis, cell apoptosis assays, and genome-wide mRNA expression profiling.
• Immunofluorescence staining for chondrogenic and osteogenic markers.

Main Results:

• Mll4-cKO mice exhibited midfacial hypoplasia, palatal midline defects, and a widened midpalatal suture.
• A transverse growth deficit in palate width was observed in Mll4-cKO mice.
• Defects originated prenatally, associated with increased apoptosis and impaired expression of cartilage genes (e.g., COL2A1, ACAN) and SOX9 in the midpalatal suture.

Conclusions:

• MLL4 is essential for proper midpalatal suture development and palate growth.
• MLL4 regulates key cellular and molecular events, including chondrogenesis, during palate development.
• The findings highlight MLL4's critical role in craniofacial development and provide insights into Kabuki syndrome pathogenesis.