title: VEGF signaling through neuropilin 1 guides commissural axon crossing at the optic chiasm.
abstract: During development, the axons of retinal ganglion cell (RGC) neurons must decide whether to cross or avoid the midline at the optic chiasm to project to targets on both sides of the brain. By combining genetic analyses with in vitro assays, we show that neuropilin 1 (NRP1) promotes contralateral RGC projection in mammals. Unexpectedly, the NRP1 ligand involved is not an axon guidance cue of the class 3 semaphorin family, but VEGF164, the neuropilin-binding isoform of the classical vascular growth factor VEGF-A. VEGF164 is expressed at the chiasm midline and is required for normal contralateral growth in vivo. In outgrowth and growth cone turning assays, VEGF164 acts directly on NRP1-expressing contralateral RGCs to provide growth-promoting and chemoattractive signals. These findings have identified a permissive midline signal for axons at the chiasm midline and provide in vivo evidence that VEGF-A is an essential axon guidance cue.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK. l.erskine@abdn.ac.uk
authors.forename: Lynda
authors.initials: L
authors.lastname: Erskine
authors.forename: Susan
authors.initials: S
authors.lastname: Reijntjes
authors.forename: Thomas
authors.initials: T
authors.lastname: Pratt
authors.forename: Laura
authors.initials: L
authors.lastname: Denti
authors.forename: Quenten
authors.initials: Q
authors.lastname: Schwarz
authors.forename: Joaquim M
authors.initials: JM
authors.lastname: Vieira
authors.forename: Bennett
authors.initials: B
authors.lastname: Alakakone
authors.forename: Derryck
authors.initials: D
authors.lastname: Shewan
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
mesh_terms: D000367:Age Factors; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects; D004622:Embryo, Mammalian; D007839:Functional Laterality; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D020439:Growth Cones / Q000502:physiology; D007211:Indoles / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039942:Neuropilin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D039943:Neuropilin-2 / Q000172:deficiency; D009897:Optic Chiasm / Q000187:drug effects / Q000196:embryology / Q000502:physiology*; D009924:Organ Culture Techniques; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D040121:Semaphorin-3A / Q000172:deficiency; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D007211:Indoles; D039943:Neuropilin-2; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C098463:dolaisoleucine; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1; C007293:DAPI; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2