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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.

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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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