Neuropilin-1 Conveys Semaphorin and VEGF Signaling During Neural and Cardiovascular Development

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2003 Jul 11

PMID 12852851

Citations 348

Authors

Chenghua Gu

E Rene Rodriguez

Dorothy V Reimert

Tianzhi Shu

Bernd Fritzsch

Linda J Richards

Alex L Kolodkin

David D Ginty

Affiliations

Soon will be listed here.

Abstract

Neuropilin-1 (Npn-1) is a receptor that binds multiple ligands from structurally distinct families, including secreted semaphorins (Sema) and vascular endothelial growth factors (VEGF). We generated npn-1 knockin mice, which express an altered ligand binding site variant of Npn-1, and npn-1 conditional null mice to establish the cell-type- and ligand specificity of Npn-1 function in the developing cardiovascular and nervous systems. Our results show that VEGF-Npn-1 signaling in endothelial cells is required for angiogenesis. In striking contrast, Sema-Npn-1 signaling is not essential for general vascular development but is required for axonal pathfinding by several populations of neurons in the CNS and PNS. Remarkably, both Sema-Npn-1 signaling and VEGF-Npn-1 signaling are critical for heart development. Therefore, Npn-1 is a multifunctional receptor that mediates the activities of structurally distinct ligands during development of the heart, vasculature, and nervous system.

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References

Giger R, Cloutier J, Sahay A, Prinjha R, Levengood D, Moore S . Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron. 2000; 25(1):29-41. DOI: 10.1016/s0896-6273(00)80869-7. View

Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z . Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999; 13(1):9-22. View

Shimizu M, Murakami Y, Suto F, Fujisawa H . Determination of cell adhesion sites of neuropilin-1. J Cell Biol. 2000; 148(6):1283-93. PMC: 2174302. DOI: 10.1083/jcb.148.6.1283. View

Polleux F, Morrow T, Ghosh A . Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature. 2000; 404(6778):567-73. DOI: 10.1038/35007001. View

Rodriguez C, Buchholz F, Galloway J, Sequerra R, Kasper J, Ayala R . High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nat Genet. 2000; 25(2):139-40. DOI: 10.1038/75973. View

Chen H, He Z, Bagri A, Tessier-Lavigne M . Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron. 1999; 21(6):1283-90. DOI: 10.1016/s0896-6273(00)80648-0. View

Takahashi T, Nakamura F, Jin Z, Kalb R, Strittmatter S . Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. Nat Neurosci. 1999; 1(6):487-93. DOI: 10.1038/2203. View

Sondell M, Lundborg G, Kanje M . Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci. 1999; 19(14):5731-40. PMC: 6783109. View

Feng G, Mellor R, Bernstein M, Nguyen Q, Wallace M, Nerbonne J . Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 2000; 28(1):41-51. DOI: 10.1016/s0896-6273(00)00084-2. View

10.

Sondell M, Sundler F, Kanje M . Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci. 2000; 12(12):4243-54. DOI: 10.1046/j.0953-816x.2000.01326.x. View

11.

Kisanuki Y, Hammer R, Miyazaki J, Williams S, Richardson J, Yanagisawa M . Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol. 2001; 230(2):230-42. DOI: 10.1006/dbio.2000.0106. View

12.

Shu T, Richards L . Cortical axon guidance by the glial wedge during the development of the corpus callosum. J Neurosci. 2001; 21(8):2749-58. PMC: 6762517. View

13.

Ferrara N . Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001; 280(6):C1358-66. DOI: 10.1152/ajpcell.2001.280.6.C1358. View

14.

Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K . Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001; 28(2):131-8. DOI: 10.1038/88842. View

15.

Pozas E, Pascual M, Guijarro P, Sotelo C, Chedotal A, Del Rio J . Age-dependent effects of secreted Semaphorins 3A, 3F, and 3E on developing hippocampal axons: in vitro effects and phenotype of Semaphorin 3A (-/-) mice. Mol Cell Neurosci. 2001; 18(1):26-43. DOI: 10.1006/mcne.2001.0999. View

16.

FEINER L, Webber A, Brown C, Lu M, Jia L, Feinstein P . Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development. 2001; 128(16):3061-70. DOI: 10.1242/dev.128.16.3061. View

17.

Brown C, FEINER L, Lu M, Li J, Ma X, Webber A . PlexinA2 and semaphorin signaling during cardiac neural crest development. Development. 2001; 128(16):3071-80. DOI: 10.1242/dev.128.16.3071. View

18.

Neufeld G, Cohen T, Shraga N, Lange T, Kessler O, Herzog Y . The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med. 2002; 12(1):13-9. DOI: 10.1016/s1050-1738(01)00140-2. View

19.

He Z, Wang K, Koprivica V, Ming G, Song H . Knowing how to navigate: mechanisms of semaphorin signaling in the nervous system. Sci STKE. 2002; 2002(119):re1. DOI: 10.1126/stke.2002.119.re1. View

20.

Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F . Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci U S A. 2002; 99(6):3657-62. PMC: 122579. DOI: 10.1073/pnas.022017899. View