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Notch signaling is an evolutionarily conserved pathway that modulates cell fate decisions, which has been shown to both inhibit and promote dermal lymphangiogenesis. Here, we demonstrate distinct roles for Notch4 signaling versus canonical Notch signaling in embryonic dermal lymphangiogenesis. Actively growing embryonic dermal lymphatics expressed NOTCH1, NOTCH4, and DLL4 which correlated with Notch activity. In lymphatic endothelial cells (LECs), DLL4 activation of Notch induced a subset of Notch effectors and lymphatic genes, which were distinctly regulated by Notch1 and Notch4 activation. Treatment of LECs with VEGF-A or VEGF-C upregulated\n                    <jats:italic>Dll4<\/jats:italic>\n                    transcripts and differentially and temporally regulated the expression of\n                    <jats:italic>Notch1<\/jats:italic>\n                    and\n                    <jats:italic>Hes<\/jats:italic>\n                    \/\n                    <jats:italic>Hey<\/jats:italic>\n                    genes. Mice nullizygous for\n                    <jats:italic>Notch4<\/jats:italic>\n                    had an increase in the closure of the lymphangiogenic fronts which correlated with reduced vessel caliber in the maturing lymphatic plexus at E14.5 and reduced branching at E16.5. Activation of Notch4 suppressed LEC migration in a wounding assay significantly more than Notch1, suggesting a dominant role for Notch4 in regulating LEC migration. Unlike\n                    <jats:italic>Notch4<\/jats:italic>\n                    nulls, inhibition of canonical Notch signaling by expressing a dominant negative form of MAML1 (DNMAML) in Prox1+ LECs led to increased lymphatic density consistent with an increase in LEC proliferation, described for the loss of LEC\n                    <jats:italic>Notch1<\/jats:italic>\n                    . Moreover, loss of\n                    <jats:italic>Notch4<\/jats:italic>\n                    did not affect LEC canonical Notch signaling. Thus, we propose that Notch4 signaling and canonical Notch signaling have distinct functions in the coordination of embryonic dermal lymphangiogenesis.\n                  <\/jats:p>","DOI":"10.1007\/s10456-021-09822-5","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T05:17:29Z","timestamp":1634620649000},"page":"205-224","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Unique functions for Notch4 in murine embryonic lymphangiogenesis"],"prefix":"10.1007","volume":"25","author":[{"given":"Ajit","family":"Muley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minji","family":"Kim Uh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glicella","family":"Salazar-De Simone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhairavi","family":"Swaminathan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer M.","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aino","family":"Murtomaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seock Won","family":"Youn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph D.","family":"McCarron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Kitajewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Gnarra Buethe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Riitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoh-suke","family":"Mukouyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kitajewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2654-3559","authenticated-orcid":false,"given":"Carrie J.","family":"Shawber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,19]]},"reference":[{"issue":"18","key":"9822_CR1","doi-asserted-by":"publisher","first-page":"3903","DOI":"10.1242\/dev.095026","volume":"140","author":"JM James","year":"2013","unstructured":"James JM, Nalbandian A, Mukouyama YS (2013) TGFbeta signaling is required for sprouting lymphangiogenesis during lymphatic network development in the skin. 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