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Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury


Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting1,2,3,4,5. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs6,7,8. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.

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Figure 1: Immobilization of growth cones within gradients of CSPG.
Figure 2: Identification and characterization of ISP.
Figure 3: Functional recovery after ISP treatment.
Figure 4: Anatomical changes after ISP treatment.


  1. Cregg, J. M. et al. Functional regeneration beyond the glial scar. Exp. Neurol. 253, 197–207 (2014)

    Article  Google Scholar 

  2. Andrews, E. M., Richards, R. J., Yin, F. Q., Viapiano, M. S. & Jakeman, L. B. Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. Exp. Neurol. 235, 174–187 (2012)

    Article  CAS  Google Scholar 

  3. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002)

    Article  CAS  ADS  Google Scholar 

  4. Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002)

    Article  CAS  ADS  Google Scholar 

  5. Massey, J. M. et al. Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J. Neurosci. 26, 4406–4414 (2006)

    Article  CAS  Google Scholar 

  6. Shen, Y. et al. PTPσ is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596 (2009)

    Article  CAS  ADS  Google Scholar 

  7. Fisher, D. et al. Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors. J. Neurosci. 31, 14051–14066 (2011)

    Article  CAS  Google Scholar 

  8. Dickendesher, T. L. et al. NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nature Neurosci. 15, 703–712 (2012)

    Article  CAS  Google Scholar 

  9. Tom, V. J., Steinmetz, M. P., Miller, J. H., Doller, C. M. & Silver, J. Studies on the development and behavior of the dystrophic growth cone, the hallmark of regeneration failure, in an in vitro model of the glial scar and after spinal cord injury. J. Neurosci. 24, 6531–6539 (2004)

    Article  CAS  Google Scholar 

  10. Busch, S. A., Horn, K. P., Silver, D. J. & Silver, J. Overcoming macrophage-mediated axonal dieback following CNS injury. J. Neurosci. 29, 9967–9976 (2009)

    Article  CAS  Google Scholar 

  11. Cajal, S. R. Y. Degeneration & Regeneration of the Nervous System (Oxford Univ. Press, 1928)

    Google Scholar 

  12. Aicher, B., Lerch, M. M., Muller, T., Schilling, J. & Ullrich, A. Cellular redistribution of protein tyrosine phosphatases LAR and PTPσ by inducible proteolytic processing. J. Cell Biol. 138, 681–696 (1997)

    Article  CAS  Google Scholar 

  13. Serra-Pagès, C. et al. The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J. 14, 2827–2838 (1995)

    Article  Google Scholar 

  14. Xie, Y. et al. Protein-tyrosine phosphatase (PTP) wedge domain peptides: a novel approach for inhibition of PTP function and augmentation of protein-tyrosine kinase function. J. Biol. Chem. 281, 16482–16492 (2006)

    Article  CAS  Google Scholar 

  15. Jiang, G. et al. Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-α. Nature 401, 606–610 (1999)

    Article  CAS  ADS  Google Scholar 

  16. Barr, A. J. et al. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell 136, 352–363 (2009)

    Article  CAS  Google Scholar 

  17. Wallace, M. J., Fladd, C., Batt, J. & Rotin, D. The second catalytic domain of protein tyrosine phosphatase δ (PTPδ) binds to and inhibits the first catalytic domain of PTPσ. Mol. Cell. Biol. 18, 2608–2616 (1998)

    Article  CAS  Google Scholar 

  18. Silver, D. J. et al. Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. J. Neurosci. 33, 15603–15617 (2013)

    Article  CAS  Google Scholar 

  19. Lowery, L. A. & Van Vactor, D. The trip of the tip: understanding the growth cone machinery. Nature Rev. Mol. Cell Biol. 10, 332–343 (2009)

    Article  CAS  Google Scholar 

  20. Polleux, F. & Snider, W. Initiating and growing an axon. Cold Spring Harb. Perspect. Biol. 2, a001925 (2010)

    Article  CAS  Google Scholar 

  21. Sapieha, P. S. et al. Receptor protein tyrosine phosphatase sigma inhibits axon regrowth in the adult injured CNS. Mol. Cell. Neurosci. 28, 625–635 (2005)

    Article  CAS  Google Scholar 

  22. Banks, W. A., Robinson, S. M. & Nath, A. Permeability of the blood–brain barrier to HIV-1 Tat. Exp. Neurol. 193, 218–227 (2005)

    Article  CAS  Google Scholar 

  23. Jones, L. L. & Tuszynski, M. H. Chronic intrathecal infusions after spinal cord injury cause scarring and compression. Microsc. Res. Tech. 54, 317–324 (2001)

    Article  CAS  Google Scholar 

  24. de Groat, W. C. et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J. Auton. Nerv. Syst. 30 (suppl.). S71–S77 (1990)

    Article  Google Scholar 

  25. Pikov, V. & Wrathall, J. R. Coordination of the bladder detrusor and the external urethral sphincter in a rat model of spinal cord injury: effect of injury severity. J. Neurosci. 21, 559–569 (2001)

    Article  CAS  Google Scholar 

  26. Lee, Y. S. et al. Nerve regeneration restores supraspinal control of bladder function after complete spinal cord injury. J. Neurosci. 33, 10591–10606 (2013)

    Article  CAS  Google Scholar 

  27. Basso, D. M., Beattie, M. S. & Bresnahan, J. C. A sensitive and reliable locomotor rating scale for open field testing in rats. J. Neurotrauma 12, 1–21 (1995)

    Article  CAS  Google Scholar 

  28. Tuszynski, M. H. & Steward, O. Concepts and methods for the study of axonal regeneration in the CNS. Neuron 74, 777–791 (2012)

    Article  CAS  Google Scholar 

  29. Murray, K. C. et al. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nature Med. 16, 694–700 (2010)

    Article  CAS  Google Scholar 

  30. Xu, B. et al. Role of CSPG receptor LAR phosphatase in restricting axon regeneration after CNS injury. Neurobiol. Dis. 73C, 36–48 (2014)

    Google Scholar 

  31. Horn, K. P., Busch, S. A., Hawthorne, A. L., van Rooijen, N. & Silver, J. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J. Neurosci. 28, 9330–9341 (2008)

    Article  CAS  Google Scholar 

  32. Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77–88 (1988)

    Article  CAS  Google Scholar 

  33. Cheng, C. L. & de Groat, W. C. The role of capsaicin-sensitive afferent fibers in the lower urinary tract dysfunction induced by chronic spinal cord injury in rats. Exp. Neurol. 187, 445–454 (2004)

    Article  CAS  Google Scholar 

  34. Jakeman, L. B. in Animal Models of Acute Neurological Injuries II (eds Chen, J. Xu, X.-M., Xu, Z. C. & Zhang, J. H. ) 417–442 (Springer, 2012).

  35. Weidner, N., Ner, A., Salimi, N. & Tuszynski, M. H. Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc. Natl Acad. Sci. USA 98, 3513–3518 (2001)

    Article  CAS  ADS  Google Scholar 

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This work was supported by National Institute of Neurological Disorders and Stroke grant NS025713 (J.S.); the Case Western Reserve University Council to Advance Human Health; P. Jing, R. Senior and S. Poon; Unite to Fight Paralysis; The Brumagin Memorial Fund; Spinal Cord Injury Sucks; United Paralysis Foundation; and The Kaneko Family Fund. The authors thank J. Flanagan, M. Blackmore, A. Filous, S. Brady-Kalnay, R. Gardner and B. Habecker for their valuable discussion and input into the project.

Author information

Authors and Affiliations



B.T.L. performed all in vitro experiments, time-lapse microscopy, ISP treatments, immunohistochemistry and data quantification. B.T.L., J.M.C. and Y.L.W. designed the peptides. M.A.D. and A.T. performed all surgical procedures. B.T.L., M.A.D., K.M.M. and A.T. performed behavioural testing. A.T., B.P.B. and K.X. helped perform the pulldowns. S.M.D. and S.K.-A. performed the CSPG signalling experiments. Y.S., S.K.-A., S.L. and S.A.B. contributed to experimental design and figure preparation. B.T.L. and J.S. designed all studies, analysed the data and wrote the paper. All authors discussed and helped prepare the manuscript.

Corresponding author

Correspondence to Jerry Silver.

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Competing interests

A preliminary patent application (61/621,623) has been filed for ISP.

Extended data figures and tables

Extended Data Figure 1 CSPG receptors LAR and NgR in vitro and PTPσ in vivo.

a, LAR expression in motile (left, on laminin) and immobilized (right, within CSPG gradient) growth cones. b, Nogo receptors in a soma and axons. Scale bars, 20 μm. c, d, PTPσ expression in the spinal cord 14 days after dorsal column crush injury. The arrowhead pointing upwards represents a labelled structure with dystrophic morphology. Scale bar, 50 μm.

Extended Data Figure 2 LAR structure, sequence alignment and pulldown analysis.

a, BLAST alignment of the known sequences of mouse, rat and human LAR, PTPσ, PTPδ and PTPμ. The wedge domain of each protein is aligned within the box. b, The tandem intracellular phosphatase domains of human LAR with the previously characterized wedge domain (red)14. c, d, Pulldown of recombinant PTPσ with biotinylated (b)ISP or ILP. e, f, Eluted lysate after pulldown was probed with antibodies against either LAR or pan-NgRs. Input is 10% lysate control.

Extended Data Figure 3 Astrocyte and satellite cell response to ISP and the adhesion assay.

a, Purified GFAP-positive mature astrocytes (green) did not respond to ISP. b, S100-positive satellite glia were able to cross the gradient of CSPG after ISP treatment. Scale bar, 50 μm. c, d, Response of neurons and axons upon a CSPG-rich substrate to agitation after ISP treatment. Scale bar, 50 μm.

Extended Data Figure 4 CSPG and ISP regulation of Erk1/2.

Western blot analysis revealed a significant decrease in the phosphorylation ratio of Erk1/2 in SH-SY5Y cells plated on laminin (2 μg ml−1) plus CSPGs (15 μg ml−1) compared with laminin-only substrates, which was reversed by either pre-treatment with ChABC (0.1 U ml−1) or 4 days of ISP treatment (2.5 μM). pErk1/2, phosphorylated Erk1/2; tErk1/2, total Erk1/2. Data normalized to laminin control. N = 4 independent experiments. *P < 0.05 versus all other conditions, one-way ANOVA, Tukey’s post-hoc test.

Extended Data Figure 5 FITC-ISP in vivo and infinite horizon impaction.

a, b, Spinal cord 1 h after subcutaneous injections of FITC-ISP or vehicle. Scale bar, 100 µM. c, Experimental design and timeline for in vivo experiment. d, e, The force and impaction velocity of all animals that received an infinite horizon contusive injury. All impactions are within 10% from the target force of 250 kdyn, with an average force of 258.2 for both ISP and vehicle.

Extended Data Figure 6 Metabolic cage analysis at 6 weeks after injury.

a, b, Void frequency and average void volume at 6 weeks after injury. n = 11 naive, 21 vehicle, 10 ILP and 26 ISP. ch, Representative smoothed metabolic cage traces of a normal animal (c) and five treated animals (vehicle (d), ILP (e) and ISP (f, h) 12 weeks after injury. Void volume is plotted (in ml) as a function of time. Scale bar, 4 h.

Extended Data Figure 7 Additional behavioural data and analyses.

a, b, Average response to thermal (Hargrave’s test) and mechanical (Von Frey test) stimuli at 12 weeks after injury (n = 11 naive, 21 vehicle, 10 ILP and 26 ISP for thermal, n = 10 vehicle, 4 ILP and 10 ISP for mechanical). ce, Correlations between recovery of each individual motor behaviour in the ISP treatment group. fh, For each behaviour, the ISP-treated animals that recovered to two standard deviations relative to vehicle mean were separated and plotted as ‘responders’ while those that did not were plotted as ‘non-responders’. The n for the responding and non-responding group for each behaviour is listed on the graph. i, An in vivo ISP dose–response plot in a single cohort of animals. A dose-dependent increase occurred in void frequency at 12 weeks after SCI.

Extended Data Figure 8 Five repetitions of in vivo experiments.

ac, The individual results of five repeats of in vivo experiments are plotted as individual cohorts of animals for BBB, gridwalk and void frequency. *P < 0.05, **P < 0.01, repeated measures two-way ANOVA, Tukey’s post-hoc test (BBB); one-way ANOVA, Kruskal–Wallis post-hoc test (gridwalk and void frequency). Black indicates ISP versus control; red indicates ISP versus ILP. n for each condition is listed.

Extended Data Figure 9 Correlation between spared tissue and behavioural recovery.

al, Spared tissue volume (as measured by GFAP-positive tissue) or area of spared white matter at the epicentre (as measured by eriochrome cyanine staining) were plotted against behavioural scores for vehicle- (af) and ISP-treated (gl) animals. Pearson’s correlation coefficient (r value) is reported for each comparison. Only animals whose spinal cord was processed and cut coronally were included in the analysis.

Extended Data Figure 10 Neurofilament staining at lumbar levels.

af, Representative caudal neurofilament expression in lumbar spinal cord. Responders are ISP animals that demonstrated functional improvement (see Fig. 3n). All images were taken using identical settings. Scale bar, 500 μm.

Supplementary information

Adult sensory neuron growth cones on laminin substrate

Time lapse microscopy of motile, highly dynamic growth cones on a uniform substrate of laminin (10μg/ml) at 5d in vitro. Image taken every 30 sec. (MOV 28700 kb)

Adult sensory neuron growth cones within the CSPG gradient

Time lapse microscopy of growth cones stabilizing and immobilized within a gradient of CSPG at 5d in vitro. Image taken every 30 sec. (MOV 28099 kb)

Adult sensory neuron growth cones within the CSPG gradient

Time lapse microscopy of growth cones immobilized and over-adhered within a gradient of CSPG at 5d in vitro. Note that collapsed growth cones can involute into blebs, which are then transported retrogradely (part 1). 22 of the 24 growth cones analyzed at 4-6 d in vitro were partially or completely immobilized within the gradient. Image taken every 30 sec. (MOV 24668 kb)

Adult sensory neuron growth cones within the CSPG gradient following ISP or ILP treatment

Time lapse microscopy of adult DRG neurons which fail to immobilize and continually reform growth cones within the CSPG gradient following treatment with either ISP (2.5μM) or ILP (2.5μM) for 5d. Image taken every 30 sec. (MOV 29363 kb)

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Lang, B., Cregg, J., DePaul, M. et al. Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature 518, 404–408 (2015).

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