title: Neuropilin 1 (NRP1) hypomorphism combined with defective VEGF-A binding reveals novel roles for NRP1 in developmental and pathological angiogenesis.
abstract: Neuropilin 1 (NRP1) is a receptor for class 3 semaphorins and vascular endothelial growth factor (VEGF) A and is essential for cardiovascular development. Biochemical evidence supports a model for NRP1 function in which VEGF binding induces complex formation between NRP1 and VEGFR2 to enhance endothelial VEGF signalling. However, the relevance of VEGF binding to NRP1 for angiogenesis in vivo has not yet been examined. We therefore generated knock-in mice expressing Nrp1 with a mutation of tyrosine (Y) 297 in the VEGF binding pocket of the NRP1 b1 domain, as this residue was previously shown to be important for high affinity VEGF binding and NRP1-VEGFR2 complex formation. Unexpectedly, this targeting strategy also severely reduced NRP1 expression and therefore generated a NRP1 hypomorph. Despite the loss of VEGF binding and attenuated NRP1 expression, homozygous Nrp1(Y297A/Y297A) mice were born at normal Mendelian ratios, arguing against NRP1 functioning exclusively as a VEGF164 receptor in embryonic angiogenesis. By overcoming the mid-gestation lethality of full Nrp1-null mice, homozygous Nrp1(Y297A/Y297A) mice revealed essential roles for NRP1 in postnatal angiogenesis and arteriogenesis in the heart and retina, pathological neovascularisation of the retina and angiogenesis-dependent tumour growth.
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.forename: Birger
authors.initials: B
authors.lastname: Herzog
authors.forename: Marwa
authors.initials: M
authors.lastname: Mahmoud
authors.forename: Maiko
authors.initials: M
authors.lastname: Yamaji
authors.forename: Alice
authors.initials: A
authors.lastname: Plein
authors.forename: Laura
authors.initials: L
authors.lastname: Denti
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
authors.forename: Ian
authors.initials: I
authors.lastname: Zachary
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001835:Body Weight / Q000235:genetics; D063646:Carcinogenesis / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000235:genetics; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen; D011485:Protein Binding; D012161:Retinal Artery / Q000473:pathology; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D010100:Oxygen
keywords: Angiogenesis; Arteriogenesis; Hindbrain; NRP1; Retina; VEGF