title: Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis.
abstract: Neuropilins (NP1 and NP2) are vascular endothelial growth factor (VEGF) receptors that mediate developmental and tumor angiogenesis. Transgenic mice, in which both NP1 and NP2 were targeted (NP1(-/-)NP2(-/-)) died in utero at E8.5. Their yolk sacs were totally avascular. Mice deficient for NP2 but heterozygous for NP1 (NP1(+/-)NP2(-/-)) or deficient for NP1 but heterozygous for NP2 (NP1(-/-)NP2(+/-)) were also embryonic lethal and survived to E10-E10.5. The E10 yolk sacs and embryos were easier to analyze for vascular phenotype than the fragile poorly formed 8.5 embryos. The vascular phenotypes of these E10 mice were very abnormal. The yolk sacs, although of normal size, lacked the larger collecting vessels and had less dense capillary networks. PECAM staining of yolk sac endothelial cells showed the absence of branching arteries and veins, the absence of a capillary bed, and the presence of large avascular spaces between the blood vessels. The embryos displayed blood vessels heterogeneous in size, large avascular regions in the head and trunk, and blood vessel sprouts that were unconnected. The embryos were about 50% the length of wild-type mice and had multiple hemorrhages. These double NP1/NP2 knockout mice had a more severe abnormal vascular phenotype than either NP1 or NP2 single knockouts. Their abnormal vascular phenotype resembled those of VEGF and VEGFR-2 knockouts. These results suggest that NRPs are early genes in embryonic vessel development and that both NP1 and NP2 are required.
authors.affiliation: Department of Internal Medicine and Therapeutics, Department of Nutrition and Physiological Chemistry, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Fumi
authors.initials: F
authors.lastname: Tashiro
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Niwa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki Ji
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitsukawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Fujisawa
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000098:blood supply* / Q000196:embryology; D017353:Gene Deletion; D005838:Genotype; D006470:Hemorrhage; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D039942:Neuropilin-1; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013194:Staining and Labeling; D015017:Yolk Sac / Q000098:blood supply* / Q000196:embryology
chemical_list: D009419:Nerve Tissue Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D039942:Neuropilin-1