A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis

Area of Science:

• Developmental Biology
• Genetics
• Craniofacial Development

Background:

• Cleft lip and/or palate (CL/P) is a common birth defect resulting from disrupted facial morphogenesis.
• Key genes like WNT, P63, and IRF6 are implicated in CL/P, but their regulatory mechanisms are not fully understood.

Purpose of the Study:

• To investigate the role of Pbx genes in facial development and their regulation of Wnt signaling.
• To elucidate the regulatory network controlling midfacial development and its connection to CL/P.

Main Methods:

• Generation of mouse models with Pbx gene deletions in cephalic ectoderm.
• Characterization of a midfacial regulatory element bound by Pbx proteins.
• Analysis of Wnt signaling, p63 regulation, and apoptosis in mutant mice.

Main Results:

• Pbx gene deficiency in mice leads to fully penetrant CL/P and altered Wnt signaling.
• Pbx proteins regulate a midfacial element controlling Wnt9b-Wnt3 expression, which in turn affects p63.
• A conserved Pbx-Wnt-p63-Irf6 regulatory module in mammalian midfacial ectoderm was identified.

Conclusions:

• Dysregulation of the Pbx-Wnt-p63-Irf6 network causes localized apoptosis suppression and CL/P.
• Targeting Wnt ectodermal expression in Pbx mutants can rescue CL/P, suggesting potential therapeutic strategies.