Murine Notch1 is required for lymphatic vascular morphogenesis during development. Issue 7 (17th April 2014)

• Record Type: Journal Article
• Authors: Fatima, Anees; Culver, Austin; Culver, Ford; Liu, Ting; Dietz, William H.; Thomson, Benjamin R.; Hadjantonakis, Anna‐Katerina; Quaggin, Susan E.; Kume, Tsutomu
• Is Part Of: Developmental dynamics. Volume 243:Issue 7(2014:Jul.)
• Page Start: 957
• Page End: 964
• Publication Date: 2014-04-17
• Subjects: Morphogenesis -- Periodicals; Anatomy -- Periodicals; Anatomie -- Périodiques; Biologie du développement -- Périodiques; 571.833
• DOI: 10.1002/dvdy.24129
• Languages: English
• ISSNs: 1058-8388

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <underline>BACKGROUND:</underline> 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 <italic>Notch1</italic> knockout mice crossed with an inducible <italic>Prox1CreER<sup>T2</sup></italic> driver. <underline>RESULTS:</underline> LEC‐specific <italic>Notch1</italic> 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 <italic>Notch1</italic>‐mutant LECs, whereas proliferation was increased. RNA‐seq analysis revealed that expression of cytokine/chemokine signaling molecules was upregulated in <italic>Notch1</italic>‐mutant LECs isolated from E15.5 dorsal skin, whereas VEGFR3, VEGFR2, VEGFC, and Gja4 (Connexin 37) were downregulated. <underline>CONCLUSIONS:</underline> The lymphatic phenotype of LEC‐specific conditional <italic>Notch1</italic> 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. <italic>Developmental Dynamics 243:957–964, 2014</italic>. © 2014 Wiley Periodicals, Inc.</p> </abstract>