Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover
De Angelis, Jessica E.; Lagendijk, Anne K.; Chen, Huijun; Tromp, Alisha; Bower, Neil I.; Tunny, Kathryn A.; Brooks, Andrew J.; Bakkers, Jeroen; Francois, Mathias; Yap, Alpha S.; Simons, Cas; Wicking, Carol; Hogan, Benjamin M.; Smith, Kelly A.
(2017) Developmental Cell, volume 40, issue 2, pp. 123 - 136
(Article)
Abstract
Angiogenesis is responsible for tissue vascularization during development, as well as in pathological contexts, including cancer and ischemia. Vascular endothelial growth factors (VEGFs) regulate angiogenesis by acting through VEGF receptors to induce endothelial cell signaling. VEGF is processed in the extracellular matrix (ECM), but the complexity of ECM control of
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VEGF signaling and angiogenesis remains far from understood. In a forward genetic screen, we identified angiogenesis defects in tmem2 zebrafish mutants that lack both arterial and venous Vegf/Vegfr/Erk signaling. Strikingly, tmem2 mutants display increased hyaluronic acid (HA) surrounding developing vessels. Angiogenesis in tmem2 mutants was rescued, or restored after failed sprouting, by degrading this increased HA. Furthermore, oligomerized HA or overexpression of Vegfc rescued angiogenesis in tmem2 mutants. Based on these data, and the known structure of Tmem2, we find that Tmem2 regulates HA turnover to promote normal Vegf signaling during developmental angiogenesis.
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Keywords: angiogenesis, extracellular matrix, hyaluronic acid, tmem2, VEGF, zebrafish, Developmental Biology, Journal Article
ISSN: 1534-5807
Publisher: Cell Press
Note: Funding Information: A.K.L. was supported by a University of Queensland Postdoctoral Fellowship, K.A.S. by an Australian Research Council (ARC) Future Fellowship (FT110100496), B.M.H. in part by an ARC Future Fellowship (FT100100165), and an National Health and Medical Research Council (NHMRC)/National Heart Foundation Career Development Fellowship (1083811), M.F. by an NHMRC Australia Career Development Fellowship (1011242), and A.Y. by an NHMRC Research Fellowship (1044041). This research was supported in part by NHMRC project grants (1046028 and 1106800). Imaging was performed in the Australian Cancer Research Foundation's Dynamic Imaging Facility at the Institute of Molecular Bioscience, established with the generous support of the Australian Cancer Research Foundation. We thank Debbie Yelon for sharing reagents, Katarzyna Koltowska and Sungmin Baek for assistance with pErk staining, Marah Heijkoop for technical assistance, and Kylie Georgas for graphic design. Publisher Copyright: © 2017
(Peer reviewed)