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Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors

Nature Neuroscience volume 1, pages 487–493 (1998)Cite this article

Abstract

Neuropilin-1 (NP-1) has been identified as a necessary component of a semaphorin D (SemD) receptor that repulses dorsal root ganglion (DRG) axons during development. SemA and SemE are related to SemD and bind to NP-1, but do not repulse DRG axons. By expressing NP-1 in retinal neurons and NP-2 in DRG neurons, we demonstrate that neuropilins are sufficient to determine the functional specificity of semaphorin responsiveness. SemA and SemE block SemD binding to NP-1 and abolish SemD repulsion in axons expressing NP-1. SemA and SemE seem to have a newly discovered protein antagonist capacity at NP-1 receptors, whereas they act as agonists at receptors containing NP-2.

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Figure 1: Specificity of semaphorin interaction with NP.
Figure 2: Differential responsiveness of DRG and sympathetic ganglion to semaphorins.
Figure 3: Collapse induced by cSemD in NP-1-expressing retinal neurons.
Figure 4: NP-2 expression sensitizes DRG neurons to SemA and SemE.
Figure 5: SemA and SemE antagonize SemD action in DRG.
Figure 6: A model for semaphorin action at neuropilin receptors showing the main features of semaphorin action.

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References

  1. Tessier-Lavigne, M. & Goodman, C. S. The molecular biology of axon guidance. Science 274, 1123 –1133 (1996).

    Article  CAS  Google Scholar 

  2. Dodd, J. & Schuchardt, A. Axon guidance: a compelling case for repelling growth cones. Cell 81, 471 –474 (1995).

    Article  CAS  Google Scholar 

  3. Kolodkin, A. L. Semaphorins: mediators of repulsive growth cone guidance. Trends Cell Biol. 6, 15–22 (1996).

    Article  CAS  Google Scholar 

  4. Püschel, A. W. The semaphorins: A family of axonal guidance molecules? Eur. J. Neurosci, 8, 1317–1321 (1996).

    Article  Google Scholar 

  5. Luo, Y., Raible, D. & Raper, J. A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993).

    Article  CAS  Google Scholar 

  6. Inagaki, S., Furuyama, T. & Iwahashi, Y. Identification of a member of mouse semaphorin family . FEBS Lett. 370, 269- 272 (1995).

    Article  CAS  Google Scholar 

  7. Luo, Y. et al. A family of molecules related to collapsin in the embryonic chick nervous system. Neuron 14, 1131– 1140 (1995).

    Article  CAS  Google Scholar 

  8. Püschel, A. W., Adams, R. H. & Betz, H. Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension. Neuron 14, 941–948 (1995).

    Article  Google Scholar 

  9. Furuyama, T. et al. Identification of a novel transmembrane semaphorin expressed on lymphocytes. J. Biol. Chem. 271, 33376 –33381 (1996).

    Article  CAS  Google Scholar 

  10. Kikuchi, K., Ishida, H. & Kimura, T. Molecular cloning of a novel member of semaphorin family genes, semaphorin Z. Mol. Brain. Res. 51, 229–237 (1997).

    Article  CAS  Google Scholar 

  11. Varela-Echavarria,A., Tucker, A., Püschel, A. W. & Guthrie, S. Motor axon subpopulations respond differentially to chemorepellents netrin-1 and semaphorin D. Neuron 18, 193– 207 (1997).

    Article  CAS  Google Scholar 

  12. Kobayashi, H., Koppel, A. M., Luo, Y. & Raper, J. A. A role for collapsin-1 in olfactory and cranial sensory axon guidance. J. Neurosci. 17, 8339–8352 (1997).

    Article  CAS  Google Scholar 

  13. Adams, R. H., Lohrum, M., Klostermann, A., Betz, H. & Püschel, A. W. The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing . EMBO J. 16, 6077–6086 (1997).

    Article  CAS  Google Scholar 

  14. Koppel, A. M., Feiner, L., Kobayashi, H. & Raper, J. A. A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members. Neuron 19, 531–537 (1997).

    Article  CAS  Google Scholar 

  15. He, Z. & Tessier-Lavigne, M. Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90, 739–751 (1997).

    Article  CAS  Google Scholar 

  16. Kolodkin, A. L. et al. Neuropilin is a semaphorin receptor. Cell 90, 753–762 (1997).

    Article  CAS  Google Scholar 

  17. Takagi, S., Tsuji, T., Amagai, T., Takamatsu, T. & Fujisawa, H. Specific cell surface labels in the visual centers of Xenopus Laevis tadpole identified using monoclonal antibodies. Dev. Biol. 122, 90–100 (1987).

    Article  CAS  Google Scholar 

  18. Takagi, S. et al. The A5 antigen, a candidate for the neuronal recognition molecule, has homologous to complement component and coagulation factors. Neuron 7, 295–307 (1991).

    Article  CAS  Google Scholar 

  19. Kitsukawa,T. et al. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19, 995–1005 (1997).

    Article  CAS  Google Scholar 

  20. Taniguchi, M. et al. Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron 19, 519–530 (1997).

    Article  CAS  Google Scholar 

  21. Chen, H., Chedotal, A., He, Z., Goodman, C. S. & Tessier-Lavigne, M. Neuropilin-2, a novel member of the neuropilin family is a high affinity receptor for the semaphorins sema E and sema IV but not sema III. Neuron 19, 547– 559 (1997).

    Article  CAS  Google Scholar 

  22. Takahashi, T., Nakamura, F. & Strittmatter, S. M. Neuronal and non-neuronal collapsin-1 binding sites in developing chick are distinct from other semaphorin binding sites. J. Neurosci. 17, 9183–9193 (1997).

    Article  CAS  Google Scholar 

  23. Feiner, L., Koppel, A. M., Kobayashi, H. & Raper, J. A. Secreted chick semaphorins bind recombinant neuropilin with similar affinities but bind different subsets of neurons in situ. Neuron 19, 539–545 (1997).

    Article  CAS  Google Scholar 

  24. Kolodkin, A. L. & Ginty, D. D. Steering clear of semaphorins: neuropilins sound the retreat. Neuron 19, 1159–1162 (1997).

    Article  CAS  Google Scholar 

  25. Takagi, S. et . alExpression of a cell adhesion molecule, neuropilin, in the developing chick nervous system. Dev. Biol. 170, 207 –222 (1995).

    Article  CAS  Google Scholar 

  26. Mccarthy, A. M., McMahon, L. & Schaffer, P. A. Herpes simplex virus type I ICP27 deletion mutants exhibit altered patterns of transcription and are DNA deficient. J. Virol. 63, 18–27 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lim, F., Hartley, D. & Starr, P. Generation of high-titer defective HSV-1 vectors using an IE 2 deletion mutant and quantitative study of expression in cultured cortical cells. Bio. Techniques 20, 460– 469 (1996).

    CAS  Google Scholar 

  28. Neve, R. L., Howe, J. R., Hong, S. & Kalb, R. G. Introduction of the glutamate receptor subunit 1 into motor neurons in vitro and in vivo using a recombinant herpes simplex virus. Neuroscience 79, 435–447 (1997).

    Article  CAS  Google Scholar 

  29. Klostermann, A., Lohrum, M., Adams, R. H. & Püschel, A. W. The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization . J. Biol. Chem. 273, 7326– 7331 (1997).

    Article  Google Scholar 

  30. Goshima, Y., Nakamura, F., Strittmatter, P. & Strittmatter, S. M. Collapsin-induced growth cone collapse mediated by an intracellular protein related to unc-33. Nature 376, 509 –514 (1995).

    Article  CAS  Google Scholar 

  31. Jin, Z. & Strittmatter, S. M. Rac1 mediates collapsin-1-induced growth cone collapse. J. Neurosci. 17, 6256 –6263 (1997).

    Article  CAS  Google Scholar 

  32. Hannum, C. H. et al. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343, 336– 340 (1990).

    Article  CAS  Google Scholar 

  33. Eisenberg, S. P. et al. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature 343, 341–346 (1990).

    Article  CAS  Google Scholar 

  34. Guidotti, A. et al. Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors . Proc. Natl Acad. Sci. USA 80, 3531– 3535 (1983).

    Article  CAS  Google Scholar 

  35. Lu, D. et al. Agouti protein is an antagonist of melanocyte-stimulating-hormone receptor. Nature 371, 799– 802 (1994).

    Article  CAS  Google Scholar 

  36. Yamada, T., Endo, R., Gotoh, M. & Hirohashi, S. Identification of semaphorin E as a non-MDR drug resistance gene of human cancers. Proc. Natl Acad. Sci. USA 94, 14713– 14718 (1997).

    Article  CAS  Google Scholar 

  37. Kawakami, A., Kitsukawa, T., Tagaki, S. & Fujisawa, H. Developmentally regulated expression of a cell surface protein, neuropilin, in mouse nervous system. J. Neurobiol. 29, 1–17 (1996).

    Article  CAS  Google Scholar 

  38. Igarashi, M., Strittmatter, S. M., Vartanian, T. & Fishman, M. C. Mediation by G proteins of signals that cause collapse of growth cones. Science 259, 77–79 (1993).

    Article  CAS  Google Scholar 

  39. Strittmatter, S. M., Igarashi, M. & Fishman, M. C. GAP-43 amino terminal peptides modulate growth cone morphology and neurite outgrowth. J. Neurosci. 14, 5503–5513 (1994).

    Article  CAS  Google Scholar 

  40. Messersmith, E. K. et al. Semaphorin III can function as a selective chemorepellent to pattern sensory projections in the spinal cord. Neuron 14, 949–959 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank H. Fujisawa (Nagoya, Japan) for sharing anti-NP antiserum, A. Kolodkin (Baltimore, Maryland) for a gift of rat NP-2a cDNA and M. Tessier-Lavigne (San Francisco, California) for providing various cDNAs of mouse NP-2 isoforms. This work was supported by grants to S. M. S. and to R. G. K. from the N. I. H. and to F. N. from the Spinal Cord Research Fund of the Paralyzed Veterans of America. S. M. S. is a John Merck Scholar in the Biology of Developmental Disorders in Children.

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  1. Department of Neurology, Yale University School of Medicine, P.O. Box 208018, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Takuya Takahashi, Fumio Nakamura, Zhao Jin, Robert G. Kalb & Stephen M. Strittmatter

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  1. Takuya Takahashi
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Correspondence to Stephen M. Strittmatter.

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Takahashi, T., Nakamura, F., Jin, Z. et al. Semaphorins A and E act as antagonists of neuropilin-1 and agonists of neuropilin-2 receptors. Nat Neurosci 1, 487–493 (1998). https://doi.org/10.1038/2203

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