Wt1 and β-catenin cooperatively regulate diaphragm development in the mouse

Area of Science:

• Developmental biology
• Organogenesis
• Molecular signaling

Background:

• The developing diaphragm has poorly characterized cell types, including the mesothelium.
• Congenital diaphragmatic hernia (CDH) is a developmental defect with high postnatal morbidity and mortality.
• Canonical Wnt signaling and beta-catenin are implicated in diaphragm development.

Purpose of the Study:

• To investigate the role of the mesothelium in diaphragm development using a Wilms Tumor 1 (Wt1) mutant mouse model.
• To explore the involvement of Wnt/beta-catenin signaling in CDH pathogenesis.

Main Methods:

• Utilized a Wt1 mutant mouse model.
• Developed and characterized a Wt1(CreERT2)-driven beta-catenin loss-of-function model.
• Administered tamoxifen to induce genetic manipulation during critical developmental windows (E10.5-E11.5).

Main Results:

• Conditional beta-catenin loss in the Wt1 lineage phenocopied Wt1 mutant diaphragm defects.
• Constitutive beta-catenin activation in Wt1 mutants rescued diaphragm defects.
• Genetic manipulations affected proliferation and apoptosis, but primarily altered diaphragm differentiation.

Conclusions:

• Mesothelial signaling plays a fundamental role in proper diaphragm formation.
• Wt1 and beta-catenin signaling pathways are critical for diaphragm development and CDH prevention.