The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function.

ABSTRACT: Norrin-induced activation of β-catenin-dependent signaling through the receptor frizzled4 in endothelial cells (ECs) is essential for establishing and maintaining blood-CNS barrier function. We sought to determine how this pathway is modulated under stress or disease conditions. Specifically, we investigated the role of p53 in endothelial blood-CNS barriers because increased abundance of the transcription factor p53 in ECs correlates with leaky CNS blood vessels in type 2 diabetes. Using transcriptomic, cell-based, and mouse genetic approaches, we identified interplay between p53 and its negative regulator MDM2 and norrin/frizzled4 signaling. Mice with an EC-specific ablation of Mdm2 showed decreased norrin/frizzled4 signaling, reduced EC proliferation and retinal angiogenesis, and

SUBMITTER: Levey J 

PROVIDER: S-EPMC12288884 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature