Skip to main content

Advertisement

SpringerLink
Log in

MiR-340 Regulates Fibrinolysis and Axon Regrowth Following Sciatic Nerve Injury

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

After peripheral nerve injury, the degenerative debris and inflammatory alterations at the injury site may block the elongation of regenerating axons to reach target organs. Tissue plasminogen activator (tPA), a serine protease, has a capability of degrading matrix molecules and cell adhesions. In this study, we found that either tPA or miR-340 was differentially expressed in the injured nerve after sciatic nerve injury, and that the expressions of tPA and miR-340 were negatively correlated to each other. Moreover, miR-340 and tPA were co-localized in sciatic nerve. miR-340 regulated tPA through direct targeting of the 3′-UTR of tPA. Functionally, over- or under-expression of miR-340 reduced or augmented the fibrinolytic activity and migration ability of cultured Schwann cells as well as tPA secretion from the cells, respectively. In rats with sciatic nerve crush injury, dysregulation of the miR-340 expression in the injury site affected the cell debris removal and axonal regrowth. Obviously, unlike many previous studies that investigate the functional impact of miRNAs on peripheral nerve regeneration in the perspective of miRNA regulation of neural cell behaviors, the present study focused on miRNA regulation of debris clearance, thus updating our understanding of the regulatory roles of miRNAs in peripheral nerve regeneration.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

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

Similar content being viewed by others

References

  1. Navarro X (2015) Functional evaluation of peripheral nerve regeneration and target reinnervation in animal models: a critical overview. Eur J Neurosci: doi: 10.1111/ejn.13033.

  2. Siconolfi LB, Seeds NW (2001) Induction of the plasminogen activator system accompanies peripheral nerve regeneration after sciatic nerve crush. J Neurosci 21(12):4336–4347

    CAS  PubMed  Google Scholar 

  3. Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto Y, Hashimoto K, Noda Y, Nitta A et al (2004) The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc Natl Acad Sci U S A 101(10):3650–3655. doi:10.1073/pnas.0306587101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vassalli JD, Sappino AP, Belin D (1991) The plasminogen activator/plasmin system. J Clin Invest 88(4):1067–1072. doi:10.1172/JCI115405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Culp WC, Brown AT, Lowery JD, Arthur MC, Roberson PK, Skinner RD (2015) Dodecafluoropentane emulsion extends window for tPA therapy in a rabbit stroke model. Mol Neurobiol 52(2):979–984. doi:10.1007/s12035-015-9243-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Miller JB, Heitsch L, Siket MS, Schrock JW, Wira CR, Lewandowski C, Madsen TE, Merck LH et al (2015) The emergency medicine debate on tPA for stroke: What Is Best for Our Patients? Efficacy in the first three hours. Acad Emerg Med 22(7):852–855. doi:10.1111/acem.12712

    Article  PubMed  Google Scholar 

  7. Akassoglou K, Kombrinck KW, Degen JL, Strickland S (2000) Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 149(5):1157–1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Siconolfi LB, Seeds NW (2003) Mice lacking tissue plasminogen activator and urokinase plasminogen activator genes show attenuated matrix metalloproteases activity after sciatic nerve crush. J Neurosci Res 74(3):430–434. doi:10.1002/jnr.10786

    Article  CAS  PubMed  Google Scholar 

  9. Zou T, Ling C, Xiao Y, Tao X, Ma D, Chen ZL, Strickland S, Song H (2006) Exogenous tissue plasminogen activator enhances peripheral nerve regeneration and functional recovery after injury in mice. J Neuropathol Exp Neurol 65(1):78–86

    Article  CAS  PubMed  Google Scholar 

  10. Jinek M, Doudna JA (2009) A three-dimensional view of the molecular machinery of RNA interference. Nature 457(7228):405–412. doi:10.1038/nature07755

    Article  CAS  PubMed  Google Scholar 

  11. Vasudevan S, Tong Y, Steitz JA (2007) Switching from repression to activation: microRNAs can up-regulate translation. Science 318(5858):1931–1934. doi:10.1126/science.1149460

    Article  CAS  PubMed  Google Scholar 

  12. Kloosterman WP, Plasterk RH (2006) The diverse functions of microRNAs in animal development and disease. Dev Cell 11(4):441–450. doi:10.1016/j.devcel.2006.09.009

    Article  CAS  PubMed  Google Scholar 

  13. Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11(9):597–610. doi:10.1038/nrg2843

    CAS  PubMed  Google Scholar 

  14. Eacker SM, Dawson TM, Dawson VL (2009) Understanding microRNAs in neurodegeneration. Nat Rev Neurosci 10(12):837–841. doi:10.1038/nrn2726

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Fineberg SK, Kosik KS, Davidson BL (2009) MicroRNAs potentiate neural development. Neuron 64(3):303–309. doi:10.1016/j.neuron.2009.10.020

    Article  CAS  PubMed  Google Scholar 

  16. Davis TH, Cuellar TL, Koch SM, Barker AJ, Harfe BD, McManus MT, Ullian EM (2008) Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J Neurosci 28(17):4322–4330. doi:10.1523/JNEUROSCI.4815-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu NK, Wang XF, Lu QB, Xu XM (2009) Altered microRNA expression following traumatic spinal cord injury. Exp Neurol 219(2):424–429. doi:10.1016/j.expneurol.2009.06.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yun B, Anderegg A, Menichella D, Wrabetz L, Feltri ML, Awatramani R (2010) MicroRNA-deficient Schwann cells display congenital hypomyelination. J Neurosci 30(22):7722–7728. doi:10.1523/JNEUROSCI.0876-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pereira JA, Baumann R, Norrmen C, Somandin C, Miehe M, Jacob C, Luhmann T, Hall-Bozic H et al (2010) Dicer in Schwann cells is required for myelination and axonal integrity. J Neurosci 30(19):6763–6775. doi:10.1523/JNEUROSCI.0801-10.2010

    Article  CAS  PubMed  Google Scholar 

  20. Viader A, Chang LW, Fahrner T, Nagarajan R, Milbrandt J (2011) MicroRNAs modulate Schwann cell response to nerve injury by reinforcing transcriptional silencing of dedifferentiation-related genes. J Neurosci 31(48):17358–17369. doi:10.1523/JNEUROSCI.3931-11.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li S, Wang X, Gu Y, Chen C, Wang Y, Liu J, Hu W, Yu B et al (2015) Let-7 microRNAs regenerate peripheral nerve regeneration by targeting nerve growth factor. Mol Ther 23(3):423–433. doi:10.1038/mt.2014.220

    Article  CAS  PubMed  Google Scholar 

  22. Yu B, Qian T, Wang Y, Zhou S, Ding G, Ding F, Gu X (2012) miR-182 inhibits Schwann cell proliferation and migration by targeting FGF9 and NTM, respectively at an early stage following sciatic nerve injury. Nucleic Acids Res 40(20):10356–10365. doi:10.1093/nar/gks750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yu B, Zhou S, Wang Y, Qian T, Ding G, Ding F, Gu X (2012) miR-221 and miR-222 promote Schwann cell proliferation and migration by targeting LASS2 after sciatic nerve injury. J Cell Sci 125(Pt 11):2675–2683. doi:10.1242/jcs.098996

    Article  CAS  PubMed  Google Scholar 

  24. Zhou S, Gao R, Hu W, Qian T, Wang N, Ding G, Ding F, Yu B et al (2014) MiR-9 inhibits Schwann cell migration by targeting Cthrc1 following sciatic nerve injury. J Cell Sci 127(Pt 5):967–976. doi:10.1242/jcs.131672

    Article  CAS  PubMed  Google Scholar 

  25. Li S, Yu B, Wang Y, Yao D, Zhang Z, Gu X (2011) Identification and functional annotation of novel microRNAs in the proximal sciatic nerve after sciatic nerve transection. Sci China Life Sci 54(9):806–812. doi:10.1007/s11427-011-4213-7

    Article  CAS  PubMed  Google Scholar 

  26. Li S, Liu Q, Wang Y, Gu Y, Liu D, Wang C, Ding G, Chen J et al (2013) Differential gene expression profiling and biological process analysis in proximal nerve segments after sciatic nerve transection. PLoS One 8(2):e57000. doi:10.1371/journal.pone.0057000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Urano T, Suzuki Y (2012) Accelerated fibrinolysis and its propagation on vascular endothelial cells by secreted and retained tPA. J Biomed Biotechnol 2012:208108. doi:10.1155/2012/208108

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yu B, Zhou S, Yi S, Gu X (2015) The regulatory roles of non-coding RNAs in nerve injury and regeneration. Prog Neurobiol 134:122–139. doi:10.1016/j.pneurobio.2015.09.006

    Article  CAS  PubMed  Google Scholar 

  29. Lee SK, Wolfe SW (2000) Peripheral nerve injury and repair. J Am Acad Orthop Surg 8(4):243–252

    Article  CAS  PubMed  Google Scholar 

  30. Darrow AL, Rickles RJ, Pecorino LT, Strickland S (1990) Transcription factor Sp1 is important for retinoic acid-induced expression of the tissue plasminogen activator gene during F9 teratocarcinoma cell differentiation. Mol Cell Biol 10(11):5883–5893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Benowitz LI, Popovich PG (2011) Inflammation and axon regeneration. Curr Opin Neurol 24(6):577–583. doi:10.1097/WCO.0b013e32834c208d

    Article  CAS  PubMed  Google Scholar 

  32. Wee Yong V (2010) Inflammation in neurological disorders: a help or a hindrance? Neuroscientist 16(4):408–420. doi:10.1177/1073858410371379

    Article  CAS  PubMed  Google Scholar 

  33. Yamashita D, Kondo T, Ohue S, Takahashi H, Ishikawa M, Matoba R, Suehiro S, Kohno S et al (2015) miR340 suppresses the stem-like cell function of glioma-initiating cells by targeting tissue plasminogen activator. Cancer Res 75(6):1123–1133. doi:10.1158/0008-5472.CAN-14-0938

    Article  CAS  PubMed  Google Scholar 

  34. Wu ZS, Wu Q, Wang CQ, Wang XN, Huang J, Zhao JJ, Mao SS, Zhang GH et al (2011) miR-340 inhibition of breast cancer cell migration and invasion through targeting of oncoprotein c-Met. Cancer 117(13):2842–2852. doi:10.1002/cncr.25860

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by National Key Basic Research Program of China (2014CB542202 and 2012AA020502), National Natural Science Foundation of China (81130080, 31300879, 81471259), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Author notes

    Authors and Affiliations

    1. Jiangsu Key Laboratory of Neuroregeneration, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, 226001, China

      Shiying Li, Ruirui Zhang, Ying Yuan, Sheng Yi, Qianqian Chen, Leilei Gong, Jie Liu, Fei Ding, Zheng Cao & Xiaosong Gu

    Authors
    1. Shiying Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Ruirui Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Ying Yuan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Sheng Yi
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Qianqian Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Leilei Gong
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Jie Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Fei Ding
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Zheng Cao
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Xiaosong Gu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Zheng Cao or Xiaosong Gu.

    Ethics declarations

    Conflict of Interest

    The authors declare that they have no competing interests.

    Additional information

    Shiying Li and Ruirui Zhang 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

    Li, S., Zhang, R., Yuan, Y. et al. MiR-340 Regulates Fibrinolysis and Axon Regrowth Following Sciatic Nerve Injury. Mol Neurobiol 54, 4379–4389 (2017). https://doi.org/10.1007/s12035-016-9965-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-016-9965-4

    Keywords

    Search

    Navigation