Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sustained axon regeneration induced by co-deletion of PTEN and SOCS3

Nature volume 480, pages 372–375 (2011)Cite this article

Subjects

Abstract

A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either phosphatase and tensin homologue (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signalling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around 2 weeks after the crush injury1,2. Here we show that, remarkably, simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as key for sustaining long-distance axon regeneration in adult CNS, a crucial step towards functional recovery.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Synergistic effects of double deletion of PTEN and SOCS3 on axon regeneration observed at 4 weeks after injury.
Figure 2: Synergistic effects of double deletion of PTEN and SOCS3 on optic nerve regeneration in a delayed treatment paradigm.
Figure 3: Activation of STAT3 in axon regeneration induced by SOCS3 deletion.
Figure 4: Independence of PTEN- and SOCS3-regulated pathways.

Similar content being viewed by others

Accession codes

Data deposits

Microarray data are deposited in Gene Expression Omnibus under accession number GSE32309.

References

  1. Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008)

    Article  ADS  CAS  Google Scholar 

  2. Smith, P. D. et al. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64, 617–623 (2009)

    Article  CAS  Google Scholar 

  3. Fawcett, J. Molecular control of brain plasticity and repair. Prog. Brain Res. 175, 501–509 (2009)

    Article  CAS  Google Scholar 

  4. Filbin, M. T. Recapitulate development to promote axonal regeneration: good or bad approach? Phil. Trans. R. Soc. B 361, 1565–1574 (2006)

    Article  CAS  Google Scholar 

  5. Fitch, M. T. & Silver, J. CNS injury, glial scars, and inflammation: inhibitory extracellular matrices and regeneration failure. Exp. Neurol. 209, 294–301 (2008)

    Article  CAS  Google Scholar 

  6. Hellal, F. et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331, 928–931 (2011)

    Article  ADS  CAS  Google Scholar 

  7. Leibinger, M. et al. Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor. J. Neurosci. 29, 14334–14341 (2009)

    Article  Google Scholar 

  8. Moore, D. L. et al. KLF family members regulate intrinsic axon regeneration ability. Science 326, 298–301 (2009)

    Article  ADS  CAS  Google Scholar 

  9. Winzeler, A. M. et al. The lipid sulfatide is a novel myelin-associated inhibitor of CNS axon outgrowth. J. Neurosci. 31, 6481–6492 (2011)

    Article  CAS  Google Scholar 

  10. Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001)

    Article  ADS  CAS  Google Scholar 

  11. Mori, H. et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature Med. 10, 739–743 (2004)

    Article  CAS  Google Scholar 

  12. Fasnacht, N. & Muller, W. Conditional gp130 deficient mouse mutants. Semin. Cell Dev. Biol. 19, 379–384 (2008)

    Article  CAS  Google Scholar 

  13. Ernst, M. & Jenkins, B. J. Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet. 20, 23–32 (2004)

    Article  CAS  Google Scholar 

  14. Park, K. K. et al. Cytokine-induced SOCS expression is inhibited by cAMP analogue: impact on regeneration in injured retina. Mol. Cell. Neurosci. 41, 313–324 (2009)

    Article  CAS  Google Scholar 

  15. Park, K., Luo, J. M., Hisheh, S., Harvey, A. R. & Cui, Q. Cellular mechanisms associated with spontaneous and ciliary neurotrophic factor-cAMP-induced survival and axonal regeneration of adult retinal ganglion cells. J. Neurosci. 24, 10806–10815 (2004)

    Article  CAS  Google Scholar 

  16. Bareyre, F. M. et al. In vivo imaging reveals a phase-specific role of STAT3 during central and peripheral nervous system axon regeneration. Proc. Natl Acad. Sci. USA 108, 6282–6287 (2011)

    Article  ADS  CAS  Google Scholar 

  17. Miao, T. et al. Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons. J. Neurosci. 26, 9512–9519 (2006)

    Article  CAS  Google Scholar 

  18. Qiu, J., Cafferty, W. B., McMahon, S. B. & Thompson, S. W. Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation. J. Neurosci. 25, 1645–1653 (2005)

    Article  CAS  Google Scholar 

  19. Aaronson, D. S. & Horvath, C. M. A road map for those who don’t know JAK-STAT. Science 296, 1653–1655 (2002)

    Article  ADS  CAS  Google Scholar 

  20. Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40, 310–322 (2010)

    Article  CAS  Google Scholar 

  21. Joset, P. et al. Rostral growth of commissural axons requires the cell adhesion molecule MDGA2. Neural Develop. 6, 22 (2011)

    Article  CAS  Google Scholar 

  22. Junghans, D., Haas, I. G. & Kemler, R. Mammalian cadherins and protocadherins: about cell death, synapses and processing. Curr. Opin. Cell Biol. 17, 446–452 (2005)

    Article  CAS  Google Scholar 

  23. Low, K., Culbertson, M., Bradke, F., Tessier-Lavigne, M. & Tuszynski, M. H. Netrin-1 is a novel myelin-associated inhibitor to axon growth. J. Neurosci. 28, 1099–1108 (2008)

    Article  CAS  Google Scholar 

  24. Hannila, S. S. & Filbin, M. T. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp. Neurol. 209, 321–332 (2008)

    Article  CAS  Google Scholar 

  25. Nix, P., Hisamoto, N., Matsumoto, K. & Bastiani, M. Axon regeneration requires coordinate activation of p38 and JNK MAPK pathways. Proc. Natl Acad. Sci. USA 108, 10738–10743 (2011)

    Article  ADS  CAS  Google Scholar 

  26. Hanz, S. & Fainzilber, M. Retrograde signaling in injured nerve–the axon reaction revisited. J. Neurochem. 99, 13–19 (2006)

    Article  CAS  Google Scholar 

  27. Hoffman, P. N. A conditioning lesion induces changes in gene expression and axonal transport that enhance regeneration by increasing the intrinsic growth state of axons. Exp. Neurol. 223, 11–18 (2010)

    Article  CAS  Google Scholar 

  28. Park, K. K., Liu, K., Hu, Y., Kanter, J. L. & He, Z. PTEN/mTOR and axon regeneration. Exp. Neurol. 223, 45–50 (2010)

    Article  CAS  Google Scholar 

  29. Abe, N., Borson, S. H., Gambello, M. J., Wang, F. & Cavalli, V. Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. J. Biol. Chem. 285, 28034–28043 (2010)

    Article  CAS  Google Scholar 

  30. Christie, K. J., Webber, C. A., Martinez, J. A., Singh, B. & Zochodne, D. W. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J. Neurosci. 30, 9306–9315 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Curry and C. Wang for technical support, H. Sasaki and F. Wang for providing Stat3f/f and Rosa-lox-STOP-lox-Tomato mice, J. Gray, M. Hemberg, J. Choi, J. Ngai and W. Wang for advice on microarray and data analysis, and J. Gray, X. He, T. Schwarz, F. Wang, W. Wang and C. Woolf for reading the manuscript. This study was supported by grants from Wings for Life (to F.S.), Miami Project to Cure Paralysis (to K.K.P.) and NEI (to Z.H.).

Author information

Authors and Affiliations

  1. and Department of Neurology, F.M. Kirby Neurobiology Center, Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Fang Sun, Stephane Belin, Gang Chen, Cecil Yeung & Zhigang He

  2. Department of Neurological Surgery, Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, 33136, Florida, USA

    Kevin K. Park

  3. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Dongqing Wang & Guoping Feng

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

    Tao Lu & Bruce A. Yankner

  5. Shiley Eye Center, University of California at San Diego, La Jolla, 92093, California, USA

    Kang Zhang

Authors
  1. Fang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin K. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephane Belin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongqing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cecil Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guoping Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bruce A. Yankner
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhigang He
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.S, K.K.P., K.Z. and Z.H. conceived and F.S., K.K.P., S.B., G.C. and C.Y. performed the experiments. D.W. and G.F. provided YFP-17 mice, F.S., T.L., B.A.Y. and Z.H. analysed gene array data. F.S., K.K.P. and Z.H. prepared the manuscript.

Corresponding author

Correspondence to Zhigang He.

Ethics declarations

Competing interests

Z.H. is a co-founder of Axonis.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-12 with legends. (PDF 2817 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, F., Park, K., Belin, S. et al. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3. Nature 480, 372–375 (2011). https://doi.org/10.1038/nature10594

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10594

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing