title: Sema3A maintains corneal avascularity during development by inhibiting Vegf induced angioblast migration.
abstract: Corneal avascularity is important for optical clarity and normal vision. However, the molecular mechanisms that prevent angioblast migration and vascularization of the developing cornea are not clear. Previously we showed that periocular angioblasts and forming ocular blood vessels avoid the presumptive cornea despite dynamic ingression of neural crest cells. In the current study, we investigate the role of Semaphorin3A (Sema3A), a cell guidance chemorepellent, on angioblast migration and corneal avascularity during development. We show that Sema3A, Vegf, and Nrp1 are expressed in the anterior eye during cornea development. Sema3A mRNA transcripts are expressed at significantly higher levels than Vegf in the lens that is positioned adjacent to the presumptive cornea. Blockade of Sema3A signaling via lens removal or injection of a synthetic Sema3A inhibitor causes ectopic migration of angioblasts into the cornea and results in its subsequent vascularization. In addition, using bead implantation, we demonstrate that exogenous Sema3A protein inhibits Vegf-induced vascularization of the cornea. In agreement with these findings, loss of Sema/Nrp1 signaling in Nrp1(Sema-) mutant mice results in ectopic angioblasts and vascularization of the embryonic mouse corneas. Altogether, our results reveal Sema3A signaling as an important cue during the establishment of corneal avascularity in both chick and mouse embryos. Our study introduces cornea development as a new model for studying the mechanisms involved in vascular patterning during embryogenesis and it also provides new insights into therapeutic potential for Sema3A in neovascular diseases.
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, TX 77005, USA.
authors.forename: Chelsey C
authors.initials: CC
authors.lastname: McKenna
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, TX 77005, USA.
authors.forename: Ana F
authors.initials: AF
authors.lastname: Ojeda
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, TX 77005, USA.
authors.forename: James
authors.initials: J
authors.lastname: Spurlin
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, TX 77005, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Kwiatkowski
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, TX 77005, USA. Electronic address: lwigale@rice.edu.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Lwigale
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002465:Cell Movement; D002478:Cells, Cultured; D002642:Chick Embryo; D003315:Cornea / Q000098:blood supply* / Q000196:embryology; D042783:Endothelial Cells; D007908:Lens, Crystalline / Q000098:blood supply* / Q000196:embryology; D051379:Mice; D018919:Neovascularization, Physiologic; D039942:Neuropilin-1 / Q000096:biosynthesis / Q000235:genetics*; D011784:Quail / Q000196:embryology; D012333:RNA, Messenger / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D039942:Neuropilin-1
keywords: Angioblast; Cornea; Eye development; Nrp1; Sema3A; Vasculogenesis; Vegf