PRDM paralogs are required for Meckel's cartilage formation during mandibular bone development

Area of Science:

• Craniofacial Development
• Molecular Biology
• Developmental Biology

Background:

• Mandibular bone development involves neural crest cells (NCCs) forming Meckel's cartilage and undergoing intramembranous ossification.
• Wnt/β-catenin signaling critically regulates osteogenic versus chondrogenic differentiation of osteochondroprogenitors.
• Chromatin remodelers play a hierarchical role in controlling gene regulatory networks during development.

Purpose of the Study:

• To investigate the function of histone methyltransferases PRDM3 and PRDM16 in murine craniofacial development.
• To determine the role of PRDM3 and PRDM16 in neural crest cell differentiation and mandibular morphogenesis.

Main Methods:

• Conditional ablation of Prdm3 and Prdm16 in NCCs using Wnt1-Cre driver.
• Histological analysis of craniofacial structures, including Meckel's cartilage and mandibular bone.
• Assessment of cell proliferation (phosphoH3) and apoptosis (cleaved caspase3), and analysis of gene expression (mRNA and protein) for Wnt/β-catenin signaling components.

Main Results:

• Ablation of Prdm3 and Prdm16 led to severe mandibular hypoplasia and absence of Meckel's cartilage.
• Histology showed increased osteoblast precursors (RUNX2+) and decreased chondrogenic cells (SOX9+), indicating a shift in cell fate.
• Elevated Wnt/β-catenin signaling components were observed, suggesting PRDM3 and PRDM16 normally restrict this pathway to promote chondrogenesis.

Conclusions:

• PRDM3 and PRDM16 are crucial for NCC differentiation towards chondrocytes during Meckel's cartilage formation.
• These chromatin remodelers regulate chondrogenesis by controlling Wnt/β-catenin signaling activity.
• Proper chondrocyte differentiation mediated by PRDM3 and PRDM16 is essential for mandibular morphogenesis.