The MDM2–p53 module modulates Wnt-Fzd4 signaling and epithelial barrier assembly
July 13
Wnt-induced activation of β-catenin–dependent signaling through the receptor Fzd4 in epithelial progenitors is essential for establishing and maintaining occluding-junction barriers during organogenesis. We asked how this pathway is tuned under metabolic stress. In particular, we examined the influence of p53 on epithelial barriers because elevated p53 in surface ectoderm correlates with barrier leakage in hyperglycemic embryos.
Using transcriptomic profiling, organoid assays, and conditional mouse genetics, we uncovered cross-regulation between p53, its negative regulator MDM2, and the Wnt-Fzd4 axis. Embryos with epithelial-specific deletion of Mdm2 displayed attenuated Wnt-Fzd4 signaling, diminished progenitor proliferation, impaired junctional maturation, and increased paracellular diffusion, all of which were largely rescued by simultaneous Trp53 ablation.
Suppression of Wnt-Fzd4 signaling and progenitor expansion by p53 was associated with reduced expression of the condensin I component NCAPH. These findings position the MDM2–p53 circuit as a pivotal modulator of Wnt-driven epithelial sealing and caution that pharmacological MDM2 inhibition could compromise barrier integrity during tissue repair. Moreover, NCAPH emerges as a downstream effector of p53 in epithelia and a candidate locus for congenital barrier-defect syndromes.