{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T14:18:40Z","timestamp":1774361920412,"version":"3.50.1"},"reference-count":73,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"894","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,7,8]]},"abstract":"<jats:p>\n            Norrin-induced activation of \u03b2-catenin\u2013dependent 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\n            <jats:italic>Mdm2<\/jats:italic>\n            showed decreased norrin\/frizzled4 signaling, reduced EC proliferation and retinal angiogenesis, and disrupted blood-retina barrier function, all of which were largely restored by concurrent\n            <jats:italic>Trp53<\/jats:italic>\n            deletion. Decreased norrin\/frizzled4 signaling and inhibition of EC proliferation in response to p53 were associated with reduced expression of the condensin I complex component non-SMC condensin I complex subunit H (NCAPH). This study identifies a regulator of norrin\/frizzled4 signaling and suggests that the clinical use of MDM2 inhibitors might impair the blood-CNS barrier. In addition, NCAPH may be a downstream effector of p53 in ECs and a candidate gene for familial exudative vitreoretinopathy (FEVR), which is caused by defects in norrin signaling.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adt0983","type":"journal-article","created":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T17:58:11Z","timestamp":1751997491000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["The MDM2-p53 axis regulates norrin\/frizzled4 signaling and blood-CNS barrier function"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1358-4047","authenticated-orcid":true,"given":"Jacklyn","family":"Levey","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA."},{"name":"Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota, 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