Skip to main content

Advertisement

Log in

Mst3b Promotes Spinal Cord Neuronal Regeneration by Promoting Growth Cone Branching Out in Spinal Cord Injury Rats

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Spinal cord injury is a severe clinical problem, and research searching activity molecular that can promote spinal cord injury repairing is very prevalent. Mst3b can promote repair of damaged peripheral nerves and the optic nerve, but has been rarely reported in spinal cord injury research. Through detecting its expression in different periods of injured spinal cord, we found that the expression of Mst3b was significantly upregulated in injured spinal cord neurons. Increasing Mst3b expression using adenovirus in vivo and in vitro promoted axonal regeneration of spinal cord neurons, which led to behavioral and electrophysiological improvement. Downregulation of Mst3b level had the adverse effects. Increasing Mst3b expression in PC12 cells resulted in an elevation of P42/44MAPK and LIMK/Cofilin activation. These results identified Mst3b as a powerful regulator for promoting spinal cord injury recovery through the P42/44MAPK and LIMK/Cofilin signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Burns AS, O’Connell C (2012) The challenge of spinal cord injury care in the developing world. J Spinal Cord Med 35–38

  2. Cripps RA, Lee BB, Wing P, Weerts E, Mackay J, Brown D (2011) A global map for traumatic spinal cord injury epidemiology: towards a living data repository for injury prevention. Spinal Cord 49:493–501

    Article  CAS  PubMed  Google Scholar 

  3. Fawcett JW et al (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45:190–205

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Buchli AD, Schwab ME (2005) Inhibition of Nogo: a key strategy to increase regeneration, plasticity and functional recovery of the lesioned central nervous system. Ann Med 37:556–567

    Article  CAS  PubMed  Google Scholar 

  7. Woolf CJ (2003) No Nogo: now where to go? Neuron 38:153–156

    Article  CAS  PubMed  Google Scholar 

  8. Harel NY, Strittmatter SM (2006) Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nat Rev Neurosci 7:603–616

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Schwab ME (2002) Repairing the injured spinal cord. Science 295:1029–1031

    Article  CAS  PubMed  Google Scholar 

  10. Varma AK et al (2013) Spinal cord injury: a review of current therapy, future treatments, and basic science frontiers. Neurochem Res 38:895–905

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617–627

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Parikh P et al (2011) Regeneration of axons in injured spinal cord by activation of bone morphogenetic protein/Smad1 signaling pathway in adult neurons. Proc Natl Acad Sci U S A 108:E99–E107

    Article  PubMed Central  PubMed  Google Scholar 

  13. Neumann S, Woolf CJ (1999) Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23:83–91

    Article  CAS  PubMed  Google Scholar 

  14. Leberer E, Dignard D, Harcus D, Thomas DY, Whiteway M (1992) The protein kinase homologue Ste20p is required to link the yeast pheromone response G-protein beta gamma subunits to downstream signalling components. EMBO J 11:4815–4824

    PubMed Central  CAS  PubMed  Google Scholar 

  15. Zhou TH et al (2000) Identification of a human brain-specific isoform of mammalian STE20-like kinase 3 that is regulated by cAMP-dependent protein kinase. J Biol Chem 275:2513–2519

    Article  CAS  PubMed  Google Scholar 

  16. Irwin N, Li YM, O’Toole JE, Benowitz LI (2006) Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth. Proc Natl Acad Sci U S A 103:18320–18325

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Zai L et al (2011) Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke. J Neurosci 31:5977–5988

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Lorber B, Howe ML, Benowitz LI, Irwin N (2009) Mst3b, an Ste20-like kinase, regulates axon regeneration in mature CNS and PNS pathways. Nat Neurosci 12:1407–1414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 39:1071–1076

    Article  CAS  PubMed  Google Scholar 

  20. Dong Q, Ji YS, Cai C, Chen ZY (2012) LIM kinase 1 (LIMK1) interacts with tropomyosin-related kinase B (TrkB) and mediates brain-derived neurotrophic factor (BDNF)-induced axonal elongation. J Biol Chem 287:41720–41731

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Yoshida Y et al (2013) Transection method for shortening the rat spine and spinal cord. Exp Ther Med 5:384–388

    PubMed Central  PubMed  Google Scholar 

  22. Taylor L, Jones L, Tuszynski MH, Blesch A (2006) Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord. J Neurosci 26:9713–9721

    Article  CAS  PubMed  Google Scholar 

  23. Lu P et al (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150:1264–1273

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Leon S, Yin Y, Nguyen J, Irwin N, Benowitz LI (2000) Lens injury stimulates axon regeneration in the mature rat optic nerve. J Neurosci 20:4615–4626

    CAS  PubMed  Google Scholar 

  25. Bareyre FM, Kerschensteiner M, Raineteau O, Mettenleiter TC, Weinmann O, Schwab ME (2004) The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat Neurosci 7:269–277

    Article  CAS  PubMed  Google Scholar 

  26. Wang Y, Zhang X, Zhang Y, Xu H, Fang G (2011) Expression and localization of IL-18 in the hypothalamic-pituitary-ovarian axis of non-pregnant, pregnant, and abortive rats. J Reprod Immunol 92:45–53

    Article  CAS  PubMed  Google Scholar 

  27. Basso DM, Beattie MS, Bresnahan JC (1996) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139:244–256

    Article  CAS  PubMed  Google Scholar 

  28. Bradbury EJ et al (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416:636–640

    Article  CAS  PubMed  Google Scholar 

  29. Xu L et al (2012) Neural stem cells enhance nerve regeneration after sciatic nerve injury in rats. Mol Neurobiol 46:265–274

    Article  CAS  PubMed  Google Scholar 

  30. Jin Y, Fischer I, Tessler A, Houle JD (2002) Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp Neurol 177:265–275

    Article  CAS  PubMed  Google Scholar 

  31. Zhao RR et al (2011) Lentiviral vectors express chondroitinase ABC in cortical projections and promote sprouting of injured corticospinal axons. J Neurosci Methods 201:228–238

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Jiang XY et al (2006) Methods for isolating highly-enriched embryonic spinal cord neurons: a comparison between enzymatic and mechanical dissociations. J Neurosci Methods 158:13–18

    Article  CAS  PubMed  Google Scholar 

  33. Rosso S et al (2004) LIMK1 regulates Golgi dynamics, traffic of Golgi-derived vesicles, and process extension in primary cultured neurons. Mol Biol Cell 15:3433–3449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Schaden H, Stuermer CA, Bahr M (1994) GAP-43 immunoreactivity and axon regeneration in retinal ganglion cells of the rat. J Neurobiol 25:1570–1578

    Article  CAS  PubMed  Google Scholar 

  35. Lowery LA, Van Vactor D (2009) The trip of the tip: understanding the growth cone machinery. Nat Rev Mol Cell Biol 10:332–343

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Marsh L, Letourneau PC (1984) Growth of neurites without filopodial or lamellipodial activity in the presence of cytochalasin B. J Cell Biol 99:2041–2047

    Article  CAS  PubMed  Google Scholar 

  37. Flynn KC et al (2012) ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron 76:1091–1107

    Article  CAS  PubMed  Google Scholar 

  38. Gao Y et al (2004) Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44:609–621

    Article  CAS  PubMed  Google Scholar 

  39. David S, Lacroix S (2003) Molecular approaches to spinal cord repair. Annu Rev Neurosci 26:411–440

    Article  CAS  PubMed  Google Scholar 

  40. Wang Y et al (2012) BDNF and NT-3 expression by using glucocorticoid-induced bicistronic expression vector pGC-BDNF-IRES-NT3 protects apoptotic cells in a cellular injury model. Brain Res 1448:137–143

    Article  CAS  PubMed  Google Scholar 

  41. Dumont RJ et al (2001) Acute spinal cord injury, part I: pathophysiologic mechanisms. Clin Neuropharmacol 24:254–264

    Article  CAS  PubMed  Google Scholar 

  42. Schwab ME, Bartholdi D (1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol Rev 76:319–370

    CAS  PubMed  Google Scholar 

  43. Ylera B et al (2009) Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon. Curr Biol 19:930–936

    Article  CAS  PubMed  Google Scholar 

  44. David S, Aguayo AJ (1981) Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:931–933

    Article  CAS  PubMed  Google Scholar 

  45. Houle JD, Tom VJ, Mayes D, Wagoner G, Phillips N, Silver J (2006) Combining an autologous peripheral nervous system “bridge” and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J Neurosci 26:7405–7415

    Article  CAS  PubMed  Google Scholar 

  46. Richardson PM, McGuinness UM, Aguayo AJ (1980) Axons from CNS neurons regenerate into PNS grafts. Nature 284:264–265

    Article  CAS  PubMed  Google Scholar 

  47. Kadoya K et al (2009) Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury. Neuron 64:165–172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Ling P, Lu TJ, Yuan CJ, Lai MD (2008) Biosignaling of mammalian Ste20-related kinases. Cell Signal 20:1237–1247

    Article  CAS  PubMed  Google Scholar 

  49. Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3 T3 cells. Cell 77:841–852

    Article  CAS  PubMed  Google Scholar 

  50. Markus A, Zhong J, Snider WD (2002) Raf and akt mediate distinct aspects of sensory axon growth. Neuron 35:65–76

    Article  CAS  PubMed  Google Scholar 

  51. Zhong J, Li X, McNamee C, Chen AP, Baccarini M, Snider WD (2007) Raf kinase signaling functions in sensory neuron differentiation and axon growth in vivo. Nat Neurosci 10:598–607

    Article  CAS  PubMed  Google Scholar 

  52. Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10:381–391

    Article  CAS  PubMed  Google Scholar 

  53. Hur Saijilafu EM, Zhou FQ (2012) Growing the growth cone: remodeling the cytoskeleton to promote axon regeneration. Trends Neurosci 35:164–174

    Article  Google Scholar 

  54. Miyamoto Y, Yamauchi J, Tanoue A, Wu C, Mobley WC (2006) TrkB binds and tyrosine-phosphorylates Tiam1, leading to activation of Rac1 and induction of changes in cellular morphology. Proc Natl Acad Sci U S A 103:10444–10449

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81171142 to F.H. and No. 81001591 to H.H.), Science and Technology Development Planning Project of Shandong Province (No. 2013G0021816 to F.H.), and the Natural Science Foundation of Shandong (No. ZR2010HQ065 to H.H.). We thank Fengchan Han for technical assistance, Xiuli Zhang for the supporting cell line, and the Electron Microscope Center for the transmission electron microscope analysis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fei Huang.

Additional information

Yuqiang Zhang and Huaiqiang Hu contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Hu, H., Tian, T. et al. Mst3b Promotes Spinal Cord Neuronal Regeneration by Promoting Growth Cone Branching Out in Spinal Cord Injury Rats. Mol Neurobiol 51, 1144–1157 (2015). https://doi.org/10.1007/s12035-014-8785-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8785-7

Keywords

Navigation