title: The Notch1-Dll4 signaling pathway regulates mouse postnatal lymphatic development.
abstract: The Notch signaling pathway plays a fundamental role during blood vessel development. Notch signaling regulates blood vessel morphogenesis by promoting arterial endothelial differentiation and providing spatial and temporal control over "tip cell" phenotype during angiogenic sprouting. Components of the Notch signaling pathway have emerged as potential regulators of lymphatic development, joining the increasing examples of blood vessel regulators that are also involved in lymphatic development. However, in mammals a role for the Notch signaling pathway during lymphatic development remains to be demonstrated. In this report, we show that blockade of Notch1 and Dll4, with specific function-blocking antibodies, results in defective postnatal lymphatic development in mice. Mechanistically, Notch1-Dll4 blockade is associated with down-regulation of EphrinB2 expression, been shown to be critically involved in VEGFR3/VEGFC signaling, resulting in reduced lymphangiogenic sprouting. In addition, Notch1-Dll4 blockade leads to compromised expression of distinct lymphatic markers and to dilation of collecting lymphatic vessels with reduced and disorganized mural cell coverage. Finally, Dll4-blockade impairs wound closure and severely affects lymphangiogenesis during the wound healing in adult mouse skin. Thus, our study demonstrates for the first time in a mammalian system that Notch1-Dll4 signaling pathway regulates postnatal lymphatic development and pathologic lymphangiogenesis.
authors.affiliation: Department of Molecular Biology, Division of Research, Genentech Inc, South San Francisco, CA 94080, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Niessen
authors.forename: Gu
authors.initials: G
authors.lastname: Zhang
authors.forename: John Brady
authors.initials: JB
authors.lastname: Ridgway
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.forename: Christian W
authors.initials: CW
authors.lastname: Siebel
authors.forename: Minhong
authors.initials: M
authors.lastname: Yan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002460:Cell Line; D036388:Ephrin-B2 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D036388:Ephrin-B2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1