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

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

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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.

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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.

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Data deposits

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

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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.).

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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

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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.

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Competing interests

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

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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

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