{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T03:08:32Z","timestamp":1788577712902,"version":"build-2803163510"},"reference-count":17,"publisher":"The Company of Biologists","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,6,15]]},"abstract":"<jats:p>Collecting lymphatic ducts contain intraluminal valves that prevent backflow. In mice, lymphatic valve morphogenesis begins at embryonic day 15.5 (E15.5). In the mesentery, Prox1 expression is high in valve-forming lymphatic endothelial cells, whereas cells of the lymphatic ducts express lower levels of Prox1. Integrin \u03b19, fibronectin EIIIA, Foxc2, calcineurin and the gap junction protein Cx37 are required for lymphatic valve formation. We show that Notch1 is expressed throughout the developing mesenteric lymphatic vessels at E16.5, and that, by E18.5, Notch1 expression becomes highly enriched in the lymphatic valve endothelial cells. Using a Notch reporter mouse, Notch activity was detected in lymphatic valves at E17.5 and E18.5. The role of Notch in lymphatic valve morphogenesis was studied using a conditional lymphatic endothelial cell driver either to delete Notch1 or to express a dominant-negative Mastermind-like (DNMAML) transgene. Deletion of Notch1 led to an expansion of Prox1high cells, a defect in Prox1high cell reorientation and a decrease in integrin \u03b19 expression at sites of valve formation. Expression of DNMAML, which blocks all Notch signaling, resulted in a more severe phenotype characterized by a decrease in valves, failure of Prox1high cells to cluster, and rounding of the nuclei and decreased fibronectin-EIIIA expression in the Prox1high cells found at valve sites. In human dermal lymphatic endothelial cells, activation of Notch1 or Notch4 induced integrin \u03b19, fibronectin EIIIA and Cx37 expression. We conclude that Notch signaling is required for proper lymphatic valve formation and regulates integrin \u03b19 and fibronectin EIIIA expression during valve morphogenesis.<\/jats:p>","DOI":"10.1242\/dev.101188","type":"journal-article","created":{"date-parts":[[2014,6,10]],"date-time":"2014-06-10T11:24:45Z","timestamp":1402399485000},"page":"2446-2451","source":"Crossref","is-referenced-by-count":58,"title":["Notch signaling functions in lymphatic valve formation"],"prefix":"10.1242","volume":"141","author":[{"given":"Aino","family":"Murtomaki","sequence":"first","affiliation":[{"name":"Department of OB\/GYN, Columbia University Medical Center, New York, NY 10032, USA"},{"name":"Division of Genetics, Department of Biosciences, Viikki Biocenter, University of Helsinki, POB 56, Helsinki FIN-00014, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minji K.","family":"Uh","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Columbia University Medical Center, New York, NY 10032, USA"},{"name":"Department of Pharmacology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Kitajewski","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Nagasaki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie J.","family":"Shawber","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kitajewski","sequence":"additional","affiliation":[{"name":"Department of OB\/GYN, Columbia University Medical Center, New York, NY 10032, USA"},{"name":"Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021052723562194300_DEV101188C1","doi-asserted-by":"publisher","first-page":"3593","DOI":"10.1242\/dev.063610","article-title":"Notch signaling: simplicity in design, versatility in function","volume":"138","author":"Andersson","year":"2011","journal-title":"Development"},{"key":"2021052723562194300_DEV101188C2","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.devcel.2009.06.017","article-title":"Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis","volume":"17","author":"Bazigou","year":"2009","journal-title":"Dev. 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