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Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells

Nature Neuroscience volume 9, pages 843–852 (2006)Cite this article

Abstract

The optic nerve, like most mature CNS pathways, does not regenerate after injury. Through unknown mechanisms, however, macrophage activation in the eye stimulates retinal ganglion cells (RGCs) to regenerate long axons beyond the site of optic nerve injury. Here we identify the calcium (Ca2+)-binding protein oncomodulin as a potent macrophage-derived growth factor for RGCs and other neurons. Oncomodulin binds to rat RGCs with high affinity in a cyclic AMP (cAMP)-dependent manner and stimulates more extensive outgrowth than other known trophic agents. Depletion of oncomodulin from macrophage-conditioned media (MCM) eliminates the axon-promoting activity of MCM. The effects of oncomodulin involve downstream signaling via Ca2+/calmodulin kinase and gene transcription. In vivo, oncomodulin released from microspheres promotes regeneration in the mature rat optic nerve. Oncomodulin also stimulates outgrowth from peripheral sensory neurons. Thus, oncomodulin is a new growth factor for neurons of the mature central and peripheral nervous systems.

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Figure 1: Oncomodulin stimulates axon regeneration in RGCs.
Figure 2: Potency and specificity of oncomodulin.
Figure 3: Oncomodulin binding to RGCs: kinetics and domain analysis.
Figure 4: The downstream effects of oncomodulin involve CaMKII and transcriptional changes.
Figure 5: Oncomodulin expression and secretion.
Figure 6: Oncomodulin promotes optic nerve regeneration in vivo.
Figure 7: Oncomodulin stimulates neurite outgrowth in DRG neurons.

References

  1. Ramon y Cajal, S. Degeneration and Regeneration of the Nervous System (Oxford Univ. Press, New York, 1991).

    Book  Google Scholar 

  2. Aguayo, A.J. et al. Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals. Philos. Trans. R. Soc. Lond. B Biol. Sci. 331, 337–343 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Chierzi, S., Strettoi, E., Cenni, M.C. & Maffei, L. Optic nerve crush: axonal responses in wild-type and bcl-2 transgenic mice. J. Neurosci. 19, 8367–8376 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Shen, S., Wiemelt, A.P., McMorris, F.A. & Barres, B.A. Retinal ganglion cells lose trophic responsiveness after axotomy. Neuron 23, 285–295 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Monsul, N.T. et al. Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp. Neurol. 186, 124–133 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Kermer, P., Klocker, N., Labes, M. & Bahr, M. Inhibition of CPP32-like proteases rescues axotomized retinal ganglion cells from secondary cell death in vivo. J. Neurosci. 18, 4656–4662 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Mey, J. & Thanos, S. Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res. 602, 304–317 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Pernet, V. & Di Polo, A. Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo. Brain (2006).

  9. Koeberle, P.D. & Ball, A.K. Effects of GDNF on retinal ganglion cell survival following axotomy. Vision Res. 38, 1505–1515 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Cheng, L., Sapieha, P., Kittlerova, P., Hauswirth, W.W. & Di Polo, A. TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J. Neurosci. 22, 3977–3986 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Zhou, Y., Pernet, V., Hauswirth, W.W. & Di Polo, A. Activation of the extracellular signal-regulated kinase 1/2 pathway by AAV gene transfer protects retinal ganglion cells in glaucoma. Mol. Ther. 12, 402–412 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Weibel, D., Cadelli, D. & Schwab, M.E. Regeneration of lesioned rat optic nerve fibers is improved after neutralization of myelin-associated neurite growth inhibitors. Brain Res. 642, 259–266 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Fischer, D., He, Z. & Benowitz, L.I. Counteracting the Nogo receptor enhances optic nerve regeneration if retinal ganglion cells are in an active growth state. J. Neurosci. 24, 1646–1651 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Lehmann, M. et al. Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Fischer, D., Petkova, V., Thanos, S. & Benowitz, L.I. Switching mature retinal ganglion cells to a robust growth state in vivo: gene expression and synergy with RhoA inactivation. J. Neurosci. 24, 8726–8740 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Koprivica, V. et al. EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310, 106–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Berry, M., Carlile, J. & Hunter, A. Peripheral nerve explants grafted into the vitreous body of the eye promote the regeneration of retinal ganglion cell axons severed in the optic nerve. J. Neurocytol. 25, 147–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Leon, S., Yin, Y., Nguyen, J., Irwin, N. & Benowitz, L.I. Lens injury stimulates axon regeneration in the mature rat optic nerve. J. Neurosci. 20, 4615–4626 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Fischer, D., Heiduschka, P. & Thanos, S. Lens-injury-stimulated axonal regeneration throughout the optic pathway of adult rats. Exp. Neurol. 172, 257–272 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Lorber, B., Berry, M. & Logan, A. Lens injury stimulates adult mouse retinal ganglion cell axon regeneration via both macrophage- and lens-derived factors. Eur. J. Neurosci. 21, 2029–2034 (2005).

    Article  PubMed  Google Scholar 

  21. Yin, Y. et al. Macrophage-derived factors stimulate optic nerve regeneration. J. Neurosci. 23, 2284–2293 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Li, Y., Irwin, N., Yin, Y., Lanser, M. & Benowitz, L.I. Axon regeneration in goldfish and rat retinal ganglion cells: differential responsiveness to carbohydrates and cAMP. J. Neurosci. 23, 7830–7838 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Lorber, B., Berry, M., Logan, A. & Tonge, D. Effect of lens lesion on neurite outgrowth of retinal ganglion cells in vitro. Mol. Cell. Neurosci. 21, 301–311 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. MacManus, J.P., Whitfield, J.F., Boynton, A.L., Durkin, J.P. & Swierenga, S.H. Oncomodulin–a widely distributed, tumour-specific, calcium-binding protein. Oncodev. Biol. Med. 3, 79–90 (1982).

    CAS  PubMed  Google Scholar 

  25. Henzl, M.T., Larson, J.D. & Agah, S. Influence of monovalent cation identity on parvalbumin divalent ion-binding properties. Biochemistry 43, 2747–2763 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Henzl, M.T., Shibasaki, O., Comegys, T.H., Thalmann, I. & Thalmann, R. Oncomodulin is abundant in the organ of Corti. Hear. Res. 106, 105–111 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Meyer-Franke, A., Kaplan, M.R., Pfrieger, F.W. & Barres, B.A. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15, 805–819 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Jo, S., Wang, E. & Benowitz, L.I. CNTF is an endogenous axon regeneration factor for mammalian retinal ganglion cells. Neuroscience 89, 579–591 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Mansour-Robaey, S., Clarke, D.B., Wang, Y.C., Bray, G.M. & Aguayo, A.J. Effects of ocular injury and administration of brain-derived neurotrophic factor on survival and regrowth of axotomized retinal ganglion cells. Proc. Natl. Acad. Sci. USA 91, 1632–1636 (1994).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Cui, Q., Yip, H.K., Zhao, R.C., So, K.F. & Harvey, A.R. Intraocular elevation of cyclic AMP potentiates ciliary neurotrophic factor-induced regeneration of adult rat retinal ganglion cell axons. Mol. Cell. Neurosci. 22, 49–61 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Barres, B.A., Silverstein, B.E., Corey, D.P. & Chun, L.L. Immunological, morphological, and electrophysiological variation among retinal ganglion cells purified by panning. Neuron 1, 791–803 (1988).

    Article  CAS  PubMed  Google Scholar 

  32. Maune, J.F., Beckingham, K., Martin, S.R. & Bayley, P.M. Circular dichroism studies on calcium binding to two series of Ca2+ binding site mutants of Drosophila melanogaster calmodulin. Biochemistry 31, 7779–7786 (1992).

    Article  CAS  PubMed  Google Scholar 

  33. Pauls, T.L., Cox, J.A. & Berchtold, M.W. The Ca2+-binding proteins parvalbumin and oncomodulin and their genes: new structural and functional findings. Biochim. Biophys. Acta 1306, 39–54 (1996).

    Article  PubMed  Google Scholar 

  34. Meyer-Franke, A. et al. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 21, 681–693 (1998).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Cai, D., Shen, Y., De Bellard, M., Tang, S. & Filbin, M.T. Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. MacMicking, J., Xie, Q.W. & Nathan, C. Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323–350 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Steinmetz, M.P. et al. Chronic enhancement of the intrinsic growth capacity of sensory neurons combined with the degradation of inhibitory proteoglycans allows functional regeneration of sensory axons through the dorsal root entry zone in the mammalian spinal cord. J. Neurosci. 25, 8066–8076 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Lu, X. & Richardson, P.M. Inflammation near the nerve cell body enhances axonal regeneration. J. Neurosci. 11, 972–978 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rapalino, O. et al. Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat. Med. 4, 814–821 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Porter, A.C. et al. M1 muscarinic receptor signaling in mouse hippocampus and cortex. Brain Res. 944, 82–89 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Buxser, S., Decker, D. & Ruppel, P. Relationship among types of nerve growth factor receptors on PC12 cells. J. Biol. Chem. 265, 12701–12710 (1990).

    CAS  PubMed  Google Scholar 

  42. Goldberg, J.L. et al. Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signaling and electrical activity. Neuron 33, 689–702 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Streilein, J.W., Wilbanks, G.A., Taylor, A. & Cousins, S. Eye-derived cytokines and the immunosuppressive intraocular microenvironment: a review. Curr. Eye Res. 11 Suppl: 41–47 (1992).

    Article  PubMed  Google Scholar 

  44. Cohen-Cory, S. & Fraser, S.E. Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo. Nature 378, 192–196 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. McKinnon, S.J. et al. Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model. Mol. Ther. 5, 780–787 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Otori, Y., Wei, J.Y. & Barnstable, C.J. Neurotoxic effects of low doses of glutamate on purified rat retinal ganglion cells. Invest. Ophthalmol. Vis. Sci. 39, 972–981 (1998).

    CAS  PubMed  Google Scholar 

  47. Hapak, R.C., Lammers, P.J., Palmisano, W.A., Birnbaum, E.R. & Henzl, M.T. Site-specific substitution of glutamate for aspartate at position 59 of rat oncomodulin. J. Biol. Chem. 264, 18751–18760 (1989).

    CAS  PubMed  Google Scholar 

  48. Flanagan, J.G. et al. Alkaline phosphatase fusions of ligands or receptors as in situ probes for staining of cells, tissues, and embryos. Methods Enzymol. 327, 19–35 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Fu, K. et al. A potential approach for decreasing the burst effect of protein from PLGA microspheres. J. Pharm. Sci. 92, 1582–1591 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gavazzi, I., Kumar, R.D., McMahon, S.B. & Cohen, J. Growth responses of different subpopulations of adult sensory neurons to neurotrophic factors in vitro. Eur. J. Neurosci. 11, 3405–3414 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Y. Li for assistance in preparing fusion proteins, H. He for designing and analyzing binding assays, M. Berry for instruction in surgical methods for DRG injections, the Harvard Microchemistry Facility for carrying out the mass spectrometry analysis, and P. Rosenberg, N. Irwin, T. Schwarz, G. Corfas and D. Goldberg for comments on the manuscript. This paper is dedicated to the memory of Yin Xuequan, who inspired Y.Y.'s scientific career. Supported by the US National Institutes of Health (EY 05690), the Patterson Family Trust, the European Commission (MOIF-CT-2004-008424) and Boston Life Sciences, Inc.

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Authors and Affiliations

  1. Department of Neurosurgery and Neurobiology Program, Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Yuqin Yin, Barbara Lorber, Toru Nakazawa, Fan Jiang & Larry I Benowitz

  2. Department of Surgery, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Yuqin Yin, Barbara Lorber & Larry I Benowitz

  3. Department of Biochemistry, 117 Schweitzer Hall, University of Missouri, Columbia, 65211, Missouri, USA

    Michael T Henzl

  4. Department of Ophthalmology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Toru Nakazawa

  5. Department of Chemical and Biomedical Engineering, E-25, Massachusetts Institute of Technology, Cambridge, 03139, Massachusetts, USA

    Tommy T Thomas & Robert Langer

  6. Program in Neuroscience, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Larry I Benowitz

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Contributions

Y.Y. isolated oncomodulin, conducted all bioassays and binding assays on RGCs, performed the immunolocalization and RT-PCR studies, prepared the oncomodulin mutant proteins, conducted in vivo experiments and initial studies on DRG neurons and drafted the manuscript. M.T.H. provided background information on oncomodulin, plasmids and recombinant protein. B.L. contributed to the in vivo and in vitro studies on DRG neurons. T.N. conducted the immunoisolation of RGCs and the P-CREB studies in vivo. T.T.T. prepared the PLGA microspheres. F.J. provided technical assistance for many studies. R.L. supervised the microsphere preparation. L.I.B. supervised the project, conducted database searches and data analyses, and prepared the final manuscript and figures.

Corresponding author

Correspondence to Larry I Benowitz.

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Competing interests

Larry Benowitz is paid for consulting to Boston Life Sciences, Inc. (BLSI), which has the commercial rights of Oncomodulin. BLSI also provided a limited amount of financial support for this research. Robert Langer is a member of the Scientific Advisory Board of BLSI.

Supplementary information

Supplementary Fig. 1

Macrophage secretion of oncomodulin vs. superoxide dismutase (SOD). (PDF 262 kb)

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Yin, Y., Henzl, M., Lorber, B. et al. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci 9, 843–852 (2006). https://doi.org/10.1038/nn1701

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