Sustained axon regeneration induced by co-deletion of pten and socs3

Sustained axon regeneration induced by co-deletion of pten and socs3


Play all audios:

Loading...

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. Access through your institution Buy or subscribe This is a preview of subscription


content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 51 print issues and online access $199.00 per year only $3.90 per issue


Learn more 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 ADDITIONAL


ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS ELK-1 REGULATES RETINAL GANGLION CELL


AXON REGENERATION AFTER INJURY Article Open access 19 October 2022 _MARCKS_ OVEREXPRESSION IN RETINAL GANGLION CELLS PROMOTES OPTIC NERVE REGENERATION Article Open access 18 December 2024


KNOCKDOWN OF PORF-2 RESTORES VISUAL FUNCTION AFTER OPTIC NERVE CRUSH INJURY Article Open access 28 August 2023 ACCESSION CODES DATA DEPOSITS Microarray data are deposited in Gene Expression


Omnibus under accession number GSE32309. REFERENCES * 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  * Smith, P. D. et al. SOCS3 deletion promotes optic nerve regeneration _in vivo_. _Neuron_ 64, 617–623 (2009) Article  CAS  Google Scholar  * Fawcett, J.


Molecular control of brain plasticity and repair. _Prog. Brain Res._ 175, 501–509 (2009) Article  CAS  Google Scholar  * 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  * 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  * 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  * 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  * Moore, D. L. et al. KLF family members regulate intrinsic axon regeneration ability. _Science_ 326, 298–301 (2009) Article  ADS  CAS  Google Scholar  *


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  * 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  * 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  * Fasnacht,


N. & Muller, W. Conditional gp130 deficient mouse mutants. _Semin. Cell Dev. Biol._ 19, 379–384 (2008) Article  CAS  Google Scholar  * Ernst, M. & Jenkins, B. J. Acquiring


signalling specificity from the cytokine receptor gp130. _Trends Genet._ 20, 23–32 (2004) Article  CAS  Google Scholar  * 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  * 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  * 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  * 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  * 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  * 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  * 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  * Joset, P. et al. Rostral growth of commissural axons requires the cell adhesion molecule MDGA2. _Neural Develop._ 6, 22 (2011) Article  CAS  Google


Scholar  * 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  * 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  * 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  * 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  * Hanz, S. & Fainzilber, M. Retrograde signaling in injured nerve–the axon reaction revisited. _J.


Neurochem._ 99, 13–19 (2006) Article  CAS  Google Scholar  * 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  * 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  * 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  * 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 * 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 * Department of Neurological Surgery, Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, 33136, Florida, USA Kevin K. Park * Department of


Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA Dongqing Wang & Guoping Feng * Department


of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA Tao Lu & Bruce A. Yankner * Shiley Eye Center, University of California at San Diego, La Jolla, 92093, California,


USA Kang Zhang Authors * Fang Sun View author publications You can also search for this author inPubMed Google Scholar * Kevin K. Park View author publications You can also search for this


author inPubMed Google Scholar * Stephane Belin View author publications You can also search for this author inPubMed Google Scholar * Dongqing Wang View author publications You can also


search for this author inPubMed Google Scholar * Tao Lu View author publications You can also search for this author inPubMed Google Scholar * Gang Chen View author publications You can also


search for this author inPubMed Google Scholar * Kang Zhang View author publications You can also search for this author inPubMed Google Scholar * Cecil Yeung View author publications You


can also search for this author inPubMed Google Scholar * Guoping Feng View author publications You can also search for this author inPubMed Google Scholar * Bruce A. Yankner View author


publications You can also search for this author inPubMed Google Scholar * Zhigang He View author publications You can also search for this author inPubMed 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 POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2


POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 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: 01 June 2011 * Accepted: 28


September 2011 * Published: 06 November 2011 * Issue Date: 15 December 2011 * DOI: https://doi.org/10.1038/nature10594 SHARE THIS ARTICLE Anyone you share the following link with will be


able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing


initiative