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Gene Review

Nrp1  -  neuropilin 1

Mus musculus

Synonyms: A5 protein, C530029I03, NP-1, NPN-1, Neuropilin-1, ...
 
 
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Disease relevance of Nrp1

 

High impact information on Nrp1

  • Loss of neuropilin function increases the number of interneurons that migrate into the striatum [6].
  • This defect was not caused by isoform-specific differences in stimulating endothelial cell proliferation or by impaired isoform-specific signaling through the Nrp1 receptor [7].
  • Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit [8].
  • Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of motor axon growth and guidance during the formation of spinal motor connections [9].
  • The murine VEGF gene is alternatively transcribed to yield the VEGF(120), VEGF(164), and VEGF(188) isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth [10].
 

Biological context of Nrp1

  • Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis [11].
  • Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation [12].
  • They also reveal that endocytosis controlled by L1/NP-1 cis and trans interactions is pivotal in Sema3A-mediated axon guidance [13].
  • Although its function remains elusive, we showed previously that the cell adhesion molecule of the immunoglobulin super family L1 associates with Neuropilin-1 (NP-1) the Sema3A-binding subunit of the receptor complex and is required for Sema3A to elicit axonal repulsive responses [13].
  • These results provide evidence that Sema3A inhibits branching morphogenesis in lung bud organ cultures via NP-1 as a receptor or a component of a possible multimeric Sema3A receptor complex [14].
 

Anatomical context of Nrp1

 

Associations of Nrp1 with chemical compounds

  • Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment [20].
  • Neuropilin (previously A5) is a cell surface glycoprotein that was originally identified in Xenopus tadpole nervous tissues [21].
  • The selected peptide, ATWLPPR, inhibited the VEGF(165) binding to NRP-1 but not to tyrosine kinase receptors, VEGFR-1 (flt-1) and KDR; nor did it bind to heparin [22].
  • The multimers are composed of disulfide-linked dimers attached noncovalently by interactions involving the meprin, A5 protein, receptor protein-tyrosine phosphatase mu (MAM) domain [23].
  • Treatment with actinomycin D totally abolished both constitutive CYP 2 A 5 expression and its inducibility, suggesting that a transcriptional component is involved [24].
 

Physical interactions of Nrp1

  • Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A [15].
  • Somatosensory axon outgrowth is repulsed when soluble semaphorin D (semD) binds to growth cone neuropilin-1 (Npn-1) [16].
  • These studies demonstrate that the L1/NP-1 complex is able to confer a biological response to Sema3A with L1 mediating receptor internalization following ligand activation [13].
  • Nrp-1 also binds the VEGF-A splice isoform VEGF165, stimulates angiogenesis, and is necessary for vascular development in the mouse [25].
 

Regulatory relationships of Nrp1

 

Other interactions of Nrp1

  • Crosslinking experiments showed that (125)I-VEGF(165) binds to both NRP1 and VEGFR2 present in decidual endothelial cells [12].
  • These results suggest that NRPs are early genes in embryonic vessel development and that both NP1 and NP2 are required [31].
  • Examination of the expression of angiogenic factors that were induced after each cycle of activation, demonstrated that Hif-1a, Nrp1, and VEGF-A were all cyclically induced after each increment of distraction [32].
  • COS-7 cells coexpressing plexin-A4 with neuropilin-1 were induced to contract by Sema3A, a member of the class 3 semaphorin [33].
  • It has been proposed that four members of the plexin A subfamily (plexin-As; plexin-A1, -A2, -A3, and -A4) and two neuropilins (neuropilin-1 and neuropilin-2) form complexes and serve as receptors for class 3 secreted semaphorins (Semas), potent neural chemorepellents [34].
 

Analytical, diagnostic and therapeutic context of Nrp1

References

  1. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Kitsukawa, T., Shimizu, M., Sanbo, M., Hirata, T., Taniguchi, M., Bekku, Y., Yagi, T., Fujisawa, H. Neuron (1997) [Pubmed]
  2. Requirement of neuropilin 1-mediated Sema3A signals in patterning of the sympathetic nervous system. Kawasaki, T., Bekku, Y., Suto, F., Kitsukawa, T., Taniguchi, M., Nagatsu, I., Nagatsu, T., Itoh, K., Yagi, T., Fujisawa, H. Development (2002) [Pubmed]
  3. Expression and regulation of neuropilin-1 in human astrocytomas. Ding, H., Wu, X., Roncari, L., Lau, N., Shannon, P., Nagy, A., Guha, A. Int. J. Cancer (2000) [Pubmed]
  4. Colocalization of neuropilin-1 and Flk-1 in retinal neovascularization in a mouse model of retinopathy. Ishihama, H., Ohbayashi, M., Kurosawa, N., Kitsukawa, T., Matsuura, O., Miyake, Y., Muramatsu, T. Invest. Ophthalmol. Vis. Sci. (2001) [Pubmed]
  5. Neuropilin receptors guide distinct phases of sensory and motor neuronal segmentation. Roffers-Agarwal, J., Gammill, L.S. Development (2009) [Pubmed]
  6. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Marín, O., Yaron, A., Bagri, A., Tessier-Lavigne, M., Rubenstein, J.L. Science (2001) [Pubmed]
  7. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Ruhrberg, C., Gerhardt, H., Golding, M., Watson, R., Ioannidou, S., Fujisawa, H., Betsholtz, C., Shima, D.T. Genes Dev. (2002) [Pubmed]
  8. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Toyofuku, T., Yoshida, J., Sugimoto, T., Zhang, H., Kumanogoh, A., Hori, M., Kikutani, H. Nat. Neurosci. (2005) [Pubmed]
  9. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Huber, A.B., Kania, A., Tran, T.S., Gu, C., De Marco Garcia, N., Lieberam, I., Johnson, D., Jessell, T.M., Ginty, D.D., Kolodkin, A.L. Neuron (2005) [Pubmed]
  10. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. Stalmans, I., Ng, Y.S., Rohan, R., Fruttiger, M., Bouché, A., Yuce, A., Fujisawa, H., Hermans, B., Shani, M., Jansen, S., Hicklin, D., Anderson, D.J., Gardiner, T., Hammes, H.P., Moons, L., Dewerchin, M., Collen, D., Carmeliet, P., D'Amore, P.A. J. Clin. Invest. (2002) [Pubmed]
  11. A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells. Barr, M.P., Byrne, A.M., Duffy, A.M., Condron, C.M., Devocelle, M., Harriott, P., Bouchier-Hayes, D.J., Harmey, J.H. Br. J. Cancer (2005) [Pubmed]
  12. Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation. Halder, J.B., Zhao, X., Soker, S., Paria, B.C., Klagsbrun, M., Das, S.K., Dey, S.K. Genesis (2000) [Pubmed]
  13. Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Castellani, V., Falk, J., Rougon, G. Mol. Cell. Neurosci. (2004) [Pubmed]
  14. Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung. Ito, T., Kagoshima, M., Sasaki, Y., Li, C., Udaka, N., Kitsukawa, T., Fujisawa, H., Taniguchi, M., Yagi, T., Kitamura, H., Goshima, Y. Mech. Dev. (2000) [Pubmed]
  15. Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A. Rohm, B., Ottemeyer, A., Lohrum, M., Püschel, A.W. Mech. Dev. (2000) [Pubmed]
  16. Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse. Nakamura, F., Tanaka, M., Takahashi, T., Kalb, R.G., Strittmatter, S.M. Neuron (1998) [Pubmed]
  17. Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. Cai, H., Reed, R.R. J. Neurosci. (1999) [Pubmed]
  18. Vascular endothelial growth factor (VEGF)-C differentially affects tumor vascular function and leukocyte recruitment: role of VEGF-receptor 2 and host VEGF-A. Kadambi, A., Mouta Carreira, C., Yun, C.O., Padera, T.P., Dolmans, D.E., Carmeliet, P., Fukumura, D., Jain, R.K. Cancer Res. (2001) [Pubmed]
  19. Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling. Beck, H., Acker, T., Püschel, A.W., Fujisawa, H., Carmeliet, P., Plate, K.H. J. Neuropathol. Exp. Neurol. (2002) [Pubmed]
  20. A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment. El-Sheikh, A., Borgstrom, P., Bhattacharjee, G., Belting, M., Edgington, T.S. Cancer Res. (2005) [Pubmed]
  21. Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. Kawakami, A., Kitsukawa, T., Takagi, S., Fujisawa, H. J. Neurobiol. (1996) [Pubmed]
  22. Antiangiogenic and antitumor activities of peptide inhibiting the vascular endothelial growth factor binding to neuropilin-1. Starzec, A., Vassy, R., Martin, A., Lecouvey, M., Di Benedetto, M., Cr??pin, M., Perret, G.Y. Life Sci. (2006) [Pubmed]
  23. Multimeric structure of the secreted meprin A metalloproteinase and characterization of the functional protomer. Ishmael, F.T., Norcum, M.T., Benkovic, S.J., Bond, J.S. J. Biol. Chem. (2001) [Pubmed]
  24. Regulation of CYP 2 A 5 induction by porphyrinogenic agents in mouse primary hepatocytes. Salonpää, P., Kottari, S., Pelkonen, O., Raunio, H. Naunyn Schmiedebergs Arch. Pharmacol. (1997) [Pubmed]
  25. Neuropilin-1 is required for endothelial tip cell guidance in the developing central nervous system. Gerhardt, H., Ruhrberg, C., Abramsson, A., Fujisawa, H., Shima, D., Betsholtz, C. Dev. Dyn. (2004) [Pubmed]
  26. Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling. Mitsui, N., Inatome, R., Takahashi, S., Goshima, Y., Yamamura, H., Yanagi, S. EMBO J. (2002) [Pubmed]
  27. Growth cone neuropilin-1 mediates collapsin-1/Sema III facilitation of antero- and retrograde axoplasmic transport. Goshima, Y., Hori, H., Sasaki, Y., Yang, T., Kagoshima-Maezono, M., Li, C., Takenaka, T., Nakamura, F., Takahashi, T., Strittmatter, S.M., Misu, Y., Kawakami, T. J. Neurobiol. (1999) [Pubmed]
  28. Neuropilin1 is a direct downstream target of Nurr1 in the developing brain stem. Hermanson, E., Borgius, L., Bergsland, M., Joodmardi, E., Perlmann, T. J. Neurochem. (2006) [Pubmed]
  29. A requirement for neuropilin-1 in embryonic vessel formation. Kawasaki, T., Kitsukawa, T., Bekku, Y., Matsuda, Y., Sanbo, M., Yagi, T., Fujisawa, H. Development (1999) [Pubmed]
  30. Distorted odor maps in the olfactory bulb of semaphorin 3A-deficient mice. Taniguchi, M., Nagao, H., Takahashi, Y.K., Yamaguchi, M., Mitsui, S., Yagi, T., Mori, K., Shimizu, T. J. Neurosci. (2003) [Pubmed]
  31. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Takashima, S., Kitakaze, M., Asakura, M., Asanuma, H., Sanada, S., Tashiro, F., Niwa, H., Miyazaki Ji, J., Hirota, S., Kitamura, Y., Kitsukawa, T., Fujisawa, H., Klagsbrun, M., Hori, M. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  32. The role of angiogenesis in a murine tibial model of distraction osteogenesis. Carvalho, R.S., Einhorn, T.A., Lehmann, W., Edgar, C., Al-Yamani, A., Apazidis, A., Pacicca, D., Clemens, T.L., Gerstenfeld, L.C. Bone (2004) [Pubmed]
  33. Identification and characterization of a novel mouse plexin, plexin-A4. Suto, F., Murakami, Y., Nakamura, F., Goshima, Y., Fujisawa, H. Mech. Dev. (2003) [Pubmed]
  34. Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. Suto, F., Ito, K., Uemura, M., Shimizu, M., Shinkawa, Y., Sanbo, M., Shinoda, T., Tsuboi, M., Takashima, S., Yagi, T., Fujisawa, H. J. Neurosci. (2005) [Pubmed]
  35. Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the kidney. Villegas, G., Tufro, A. Mech. Dev. (2002) [Pubmed]
 
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