Abstract
The proliferation and migration of Schwann cells are critical for the repair and regeneration of injured peripheral nerves. Noncoding RNAs, especially microRNAs (miRNAs), have been demonstrated to participate in regulating the biological behaviors of Schwann cells. Numerous differentially expressed novel miRNAs have been identified in the injured sciatic nerve stumps previously by Solexa sequencing. In the current research, we studied the biological function of a novel miRNA, miR-sc4, in detail. Outcomes from proliferation and migration assays suggested that miR-sc4 played an inhibitory role on the proliferation and migration of Schwann cells. Results from bioinformatic analysis, luciferase reporter assay, and rescue experiments suggested that miR-sc4 executed its effect through directly targeting cyclin-dependent kinase 5 activator 1 (Cdk5r1). Collectively, our current study revealed the biological functions of a novel miRNA, showed the effect of miR-sc4 in Schwann cell phenotypic changes, and thus indicated the involvement of miRNAs in peripheral nerve repair and regeneration.
Similar content being viewed by others
References
Boerboom A, Dion V, Chariot A, Franzen R (2017) Molecular mechanisms involved in Schwann cell plasticity. Front Mol Neurosci 10:38. https://doi.org/10.3389/fnmol.2017.00038
Jessen KR, Mirsky R (2005) The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci 6:671–682. https://doi.org/10.1038/nrn1746
Bhatheja K, Field J (2006) Schwann cells: origins and role in axonal maintenance and regeneration. Int J Biochem Cell Biol 38:1995–1999. https://doi.org/10.1016/j.biocel.2006.05.007
Barton MJ, John JS, Clarke M, Wright A, Ekberg J (2017) The glia response after peripheral nerve injury: a comparison between Schwann cells and olfactory ensheathing cells and their uses for neural regenerative therapies. Int J Mol Sci. https://doi.org/10.3390/ijms18020287
Sullivan R, Dailey T, Duncan K, Abel N, Borlongan CV (2016) Peripheral nerve injury: stem cell therapy and peripheral nerve transfer. Int J Mol Sci. https://doi.org/10.3390/ijms17122101
Stoll G, Muller HW (1999) Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol 9:313–325
Frostick SP, Yin Q, Kemp GJ (1998) Schwann cells, neurotrophic factors, and peripheral nerve regeneration. Microsurgery 18:397–405
Castelnovo LF, Bonalume V, Melfi S, Ballabio M, Colleoni D, Magnaghi V (2017) Schwann cell development, maturation and regeneration: a focus on classic and emerging intracellular signaling pathways. Neural Regen Res 12:1013–1023. https://doi.org/10.4103/1673-5374.211172
Yun B, Anderegg A, Menichella D, Wrabetz L, Feltri ML, Awatramani R (2010) MicroRNA-deficient Schwann cells display congenital hypomyelination. J Neurosci 30:7722–7728. https://doi.org/10.1523/JNEUROSCI.0876-10.2010
Pereira JA, Baumann R, Norrmen C, Somandin C, Miehe M, Jacob C, Luhmann T, Hall-Bozic H, Mantei N, Meijer D, Suter U (2010) Dicer in Schwann cells is required for myelination and axonal integrity. J Neurosci 30:6763–6775. https://doi.org/10.1523/JNEUROSCI.0801-10.2010
Dugas JC, Notterpek L (2011) MicroRNAs in oligodendrocyte and Schwann cell differentiation. Dev Neurosci 33:14–20. https://doi.org/10.1159/000323919
Li S, Qian T, Wang X, Liu J, Gu X (2017) Noncoding RNAs and their potential therapeutic applications in tissue engineering. Engineering 3:3–15
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 40:10356–10365. https://doi.org/10.1093/nar/gks750
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 125:2675–2683. https://doi.org/10.1242/jcs.098996
Li S, Wang X, Gu Y, Chen C, Wang Y, Liu J, Hu W, Yu B, Wang Y, Ding F, Liu Y, Gu X (2015) Let-7 microRNAs regenerate peripheral nerve regeneration by targeting nerve growth factor. Mol Ther 23:423–433. https://doi.org/10.1038/mt.2014.220
Yi S, Yuan Y, Chen Q, Wang X, Gong L, Liu J, Gu X, Li S (2016) Regulation of Schwann cell proliferation and migration by miR-1 targeting brain-derived neurotrophic factor after peripheral nerve injury. Sci Rep 6:29121. https://doi.org/10.1038/srep29121
Li S, Zhang R, Yuan Y, Yi S, Chen Q, Gong L, Liu J, Ding F, Cao Z, Gu X (2017) MiR-340 regulates fibrinolysis and axon regrowth following sciatic nerve injury. Mol Neurobiol 54:4379–4389. https://doi.org/10.1007/s12035-016-9965-4
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 54:806–812. https://doi.org/10.1007/s11427-011-4213-7
Yi S, Wang S, Zhao Q, Yao C, Gu Y, Liu J, Gu X, Li S (2016) miR-sc3, a novel microRNA, promotes Schwann cell proliferation and migration by targeting Astn1. Cell Transpl 25:973–982. https://doi.org/10.3727/096368916X690520
Gu Y, Chen C, Yi S, Wang S, Gong L, Liu J, Gu X, Zhao Q, Li S (2015) miR-sc8 inhibits Schwann cell proliferation and migration by targeting Egfr. PLoS ONE 10:e0145185. https://doi.org/10.1371/journal.pone.0145185
Li S, Liu Q, Wang Y, Gu Y, Liu D, Wang C, Ding G, Chen J, Liu J, Gu X (2013) Differential gene expression profiling and biological process analysis in proximal nerve segments after sciatic nerve transection. PLoS ONE 8:e57000. https://doi.org/10.1371/journal.pone.0057000
Gu X, Ding F, Yang Y, Liu J (2011) Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration. Prog Neurobiol 93:204–230. https://doi.org/10.1016/j.pneurobio.2010.11.002
Asplund M, Nilsson M, Jacobsson A, von Holst H (2009) Incidence of traumatic peripheral nerve injuries and amputations in Sweden between 1998 and 2006. Neuroepidemiology 32:217–228. https://doi.org/10.1159/000197900
Aloe L, Rocco ML, Bianchi P, Manni L (2012) Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med 10:239. https://doi.org/10.1186/1479-5876-10-239
Manni L, Rocco ML, Bianchi P, Soligo M, Guaragna M, Barbaro SP, Aloe L (2013) Nerve growth factor: basic studies and possible therapeutic applications. Growth Factors 31:115–122. https://doi.org/10.3109/08977194.2013.804073
Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371:419–423. https://doi.org/10.1038/371419a0
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615–622. https://doi.org/10.1038/45159
Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471–483
Shukla V, Skuntz S, Pant HC (2012) Deregulated Cdk5 activity is involved in inducing Alzheimer’s disease. Arch Med Res 43:655–662. https://doi.org/10.1016/j.arcmed.2012.10.015
Yi S, Tang X, Yu J, Liu J, Ding F, Gu X (2017) Microarray and qPCR analyses of wallerian degeneration in rat sciatic nerves. Front Cell Neurosci 11:22. https://doi.org/10.3389/fncel.2017.00022
Meyer DA, Torres-Altoro MI, Tan Z, Tozzi A, Di Filippo M, DiNapoli V, Plattner F, Kansy JW, Benkovic SA, Huber JD, Miller DB, Greengard P, Calabresi P, Rosen CL, Bibb JA (2014) Ischemic stroke injury is mediated by aberrant Cdk5. J Neurosci 34:8259–8267. https://doi.org/10.1523/JNEUROSCI.4368-13.2014
Tan X, Chen Y, Li J, Li X, Miao Z, Xin N, Zhu J, Ge W, Feng Y, Xu X (2015) The inhibition of Cdk5 activity after hypoxia/ischemia injury reduces infarct size and promotes functional recovery in neonatal rats. Neuroscience 290:552–560. https://doi.org/10.1016/j.neuroscience.2015.01.054
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. https://doi.org/10.1016/j.pneurobio.2015.09.006
Funding
This study was supported by the Natural Science Foundation of Jiangsu Province, China (BK20150409); Pre-research Project Funding of Nantong University (16ZY13); Scientific Research Project Funding of Nantong University (Project Code: 13260128); Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17-1910); and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
Author information
Authors and Affiliations
Contributions
Conceived and designed the experiments: TQ and SY: Performed the experiments: TQ, XW, YW, PW, QL, and SY: Analyzed the data: TQ, XW, and SY: Contributed to applying reagents/materials/analysis tools: SY; Wrote the manuscript: TQ, XW, JL, and SY.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Tianmei Qian and Xinghui Wang have equal contribution to this work.
Rights and permissions
About this article
Cite this article
Qian, T., Wang, X., Wang, Y. et al. Novel miR-sc4 regulates the proliferation and migration of Schwann cells by targeting Cdk5r1. Mol Cell Biochem 447, 209–215 (2018). https://doi.org/10.1007/s11010-018-3305-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-018-3305-0