BACKGROUND: The transmembrane receptor Notch1 is a critical regulator of arterial differentiation and blood vessel sprouting. Recent evidence shows that functional blockade of Notch1 and its ligand, Dll4, leads to postnatal lymphatic defects in mice. However, the precise role of the Notch signaling pathway in lymphatic vessel development has yet to be defined. Here we show the developmental role of Notch1 in lymphatic vascular morphogenesis by analyzing lymphatic endothelial cell (LEC)-specific conditional Notch1 knockout mice crossed with an inducible Prox1CreER(T2) driver. RESULTS: LEC-specific Notch1 mutant embryos exhibited enlarged lymphatic vessels. The phenotype of lymphatic overgrowth accords with increased LEC sprouting from the lymph sacs and increased filopodia formation. Furthermore, cell death was significantly reduced in Notch1-mutant LECs, whereas proliferation was increased. RNA-seq analysis revealed that expression of cytokine/chemokine signaling molecules was upregulated in Notch1-mutant LECs isolated from E15.5 dorsal skin, whereas VEGFR3, VEGFR2, VEGFC, and Gja4 (Connexin 37) were downregulated. CONCLUSIONS: The lymphatic phenotype of LEC-specific conditional Notch1 mouse mutants indicates that Notch activity in LECs controls lymphatic sprouting and growth during development. These results provide evidence that similar to postnatal and pathological lymphatic vessel formation, the Notch signaling pathway plays a role in inhibiting developmental lymphangiogenesis.
BACKGROUND: The transmembrane receptor Notch1 is a critical regulator of arterial differentiation and blood vessel sprouting. Recent evidence shows that functional blockade of Notch1 and its ligand, Dll4, leads to postnatal lymphatic defects in mice. However, the precise role of the Notch signaling pathway in lymphatic vessel development has yet to be defined. Here we show the developmental role of Notch1 in lymphatic vascular morphogenesis by analyzing lymphatic endothelial cell (LEC)-specific conditional Notch1 knockout mice crossed with an inducible Prox1CreER(T2) driver. RESULTS: LEC-specific Notch1 mutant embryos exhibited enlarged lymphatic vessels. The phenotype of lymphatic overgrowth accords with increased LEC sprouting from the lymph sacs and increased filopodia formation. Furthermore, cell death was significantly reduced in Notch1-mutant LECs, whereas proliferation was increased. RNA-seq analysis revealed that expression of cytokine/chemokine signaling molecules was upregulated in Notch1-mutant LECs isolated from E15.5 dorsal skin, whereas VEGFR3, VEGFR2, VEGFC, and Gja4 (Connexin 37) were downregulated. CONCLUSIONS: The lymphatic phenotype of LEC-specific conditional Notch1mouse mutants indicates that Notch activity in LECs controls lymphatic sprouting and growth during development. These results provide evidence that similar to postnatal and pathological lymphatic vessel formation, the Notch signaling pathway plays a role in inhibiting developmental lymphangiogenesis.
Authors: Xabier L Aranguren; Manu Beerens; Giulia Coppiello; Cornelia Wiese; Ine Vandersmissen; Antonio Lo Nigro; Catherine M Verfaillie; Manfred Gessler; Aernout Luttun Journal: J Cell Sci Date: 2013-01-23 Impact factor: 5.285
Authors: Michael Dellinger; Robert Hunter; Michael Bernas; Nicholas Gale; George Yancopoulos; Robert Erickson; Marlys Witte Journal: Dev Biol Date: 2008-04-27 Impact factor: 3.582
Authors: Jerome W Breslin; Ying Yang; Joshua P Scallan; Richard S Sweat; Shaquria P Adderley; Walter L Murfee Journal: Compr Physiol Date: 2018-12-13 Impact factor: 9.090
Authors: Benjamin R Thomson; Stefan Heinen; Marie Jeansson; Asish K Ghosh; Anees Fatima; Hoon-Ki Sung; Tuncer Onay; Hui Chen; Shinji Yamaguchi; Aris N Economides; Ann Flenniken; Nicholas W Gale; Young-Kwon Hong; Amani Fawzi; Xiaorong Liu; Tsutomu Kume; Susan E Quaggin Journal: J Clin Invest Date: 2014-09-09 Impact factor: 14.808