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

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.

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

“…While Nrp-1 is not required for VEGF function, 7 it is necessary for Sema3A-mediated signal transduction. 30,31 To determine if Nrp-1 is required for Sema3A-mediated VP, we generated tamoxifeninducible endothelial-specific Nrp-1 knockout mice by crossing the previously described conditional Nrp-1 knockout mice (Nrp-1 fl/fl ) 8 with inducible-Cre transgenic mice where the tamoxifen-inducible Cre-ER T recombinase is driven by the 5Ј endothelial enhancer of the stem cell leukemia (EC-SCL) locus. This promoter was previously shown to induce specific expression of Cre ER T in adult endothelial cells.…”

“…8,10 In shifting the Nrp-1 pool away from VEGF signaling, Sema3A through its plexin receptors may be activating distinct pathways that interfere with VEGF-induced angiogenesis. The plexin receptors responsible for Sema3A signaling, plexinA1-A4 and plexinD1, are found in endothelial cells and may also serve as signaling receptors for Sema3A in blood vessels.…”

“…3,7 Moreover, Nrp-1 is necessary for vessel development, since Nrp-1 knockouts have impaired angiogenesis and cardiovascular development 8,9 and antibodies directed against Nrp-1 abrogate vessel remodeling. 10 While Nrp-1 is not required for VEGF function, it can enhance signaling of VEGF through one of its receptor tyrosine kinases VEGFR2.…”

Pulmonary Epithelial Neuropilin-1 Deletion Enhances Development of Cigarette Smoke–induced Emphysema

“…Inducible lung cell-specific deletion of Nrp1 was achieved using the Cre-lox system (43). Details regarding the generation of mice for these experiments are provided in the online supplement.…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…50 The analysis of neuropilin-1 knockout mice has confirmed that neuropilin-1/ VEGF interaction is required for normal development of the vasculature. 51 A soluble neuropilin-1 isoform was identified and found to have robust antitumor activity. 52 Recently, two other soluble forms of neuropilin-1, sIIINRP1 and sIVNRP1, generated by alternative splicing, were discovered and both are expressed in human cancerous tissue.…”