{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T10:44:46Z","timestamp":1781347486892,"version":"3.54.1"},"reference-count":67,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":55,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Foundation","award":["2114950"],"award-info":[{"award-number":["2114950"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01GM079428"],"award-info":[{"award-number":["R01GM079428"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:p>\n                    Adams-Oliver syndrome (AOS) is a rare congenital disorder characterized by scalp, limb, and cardiovascular defects. Although variants in the NOTCH1 receptor, DLL4 ligand, and RBPJ transcription factor have been implicated in AOS, the driving tissue types and molecular mechanisms by which these variants cause pathogenesis are unknown. Here, we used quantitative binding assays to show that AOS-associated RBPJ missense variants compromise DNA binding but not cofactor binding. These findings suggest that AOS-associated RBPJ variants do not function as loss-of-function alleles but instead act as dominant-negative proteins that sequester cofactors from DNA. Consistent with this idea, mice carrying an AOS-associated\n                    <jats:italic>Rbpj<\/jats:italic>\n                    allele develop dominant phenotypes that include increased lethality and cardiovascular defects in a\n                    <jats:italic>Notch1<\/jats:italic>\n                    heterozygous background, whereas\n                    <jats:italic>Notch1<\/jats:italic>\n                    and\n                    <jats:italic>Rbpj<\/jats:italic>\n                    compound heterozygous null alleles are well tolerated. To facilitate studies into the tissues driving AOS pathogenesis, we employed conditional genetics to isolate the contribution of the vascular endothelium to the development of AOS-like phenotypes. Importantly, our studies show that expression of the\n                    <jats:italic>Rbpj<\/jats:italic>\n                    AOS allele in endothelial cells is both necessary and sufficient to cause lethality and cardiovascular defects. These data establish that reduced Notch1 signaling in the vasculature is a key driver of pathogenesis in this AOS mouse model.\n                  <\/jats:p>","DOI":"10.1172\/jci187532","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T16:01:10Z","timestamp":1759852870000},"source":"Crossref","is-referenced-by-count":2,"title":["Defective Notch1 signaling in endothelial cells drives pathogenesis in a mouse model of Adams-Oliver syndrome"],"prefix":"10.1172","volume":"135","author":[{"given":"Alyssa F.","family":"Solano","sequence":"first","affiliation":[{"name":"Division of Developmental Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio, USA."},{"name":"Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA."},{"name":"Graduate Program in Molecular and Developmental Biology, Cincinnati Children\u2019s Hospital Research Foundation, Cincinnati, Ohio, 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