title: NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells.
abstract: Sprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis.
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fantin
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Lampropoulou
authors.affiliation: UCL Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Gaia
authors.initials: G
authors.lastname: Gestri
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Raimondi
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Senatore
authors.affiliation: UCL Division of Medicine, University College London, 5 University Street, London WC1E 6JJ, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Zachary
authors.affiliation: UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK. Electronic address: c.ruhrberg@ucl.ac.uk.
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism*; D011554:Pseudopodia / Q000378:metabolism*; D012249:Rhombencephalon / Q000098:blood supply / Q000166:cytology; D015398:Signal Transduction; D015027:Zebrafish; D020764:cdc42 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: C581598:Cdc42 protein, mouse; D039942:Neuropilin-1; D020764:cdc42 GTP-Binding Protein