miR-9 inhibits Schwann cell migration by targeting Cthrc1 following sciatic nerve injury

ABSTRACT The regulative effects of microRNAs (miRNAs) on responses of Schwann cells to a nerve injury stimulus are not yet clear. In this study, we noted that the expression of eight miRNAs was downregulated at different time points following rat sciatic nerve transection, and found that 368 potential targets of these eight miRNAs were mainly involved in phenotypic modulation of Schwann cells. Of these miRNAs, miR-9 was identified as an important functional regulator of Schwann cell migration that was a crucial regenerative response of Schwann cells to nerve injury. In vitro, upregulated expression of miR-9 inhibited Schwann cell migration, whereas silencing of miR-9 promoted Schwann cell migration. Intriguingly, miR-9 exerted this regulative function by directly targeting collagen triple helix repeat containing protein 1 (CTHRC1), which in turn inactivated downstream Rac1 GTPase. Rac1 inhibitor reduced the promotive effects of anti-miR-9 on Schwann cell migration. In vivo, high expression of miR-9 reduced Schwann cell migration within a regenerative nerve microenvironment. Collectively, our results confirmed the role of miR-9 in regulating Schwann cell migration after nerve injury, thus offering a new approach to peripheral nerve repair.

[1]  H. Okano,et al.  MicroRNAs in Neural Stem Cells and Neurogenesis , 2012, Front. Neurosci..

[2]  Ronald Deumens,et al.  Repairing injured peripheral nerves: Bridging the gap , 2010, Progress in Neurobiology.

[3]  Xiao‐hui Huang,et al.  MicroRNA-9 reduces cell invasion and E-cadherin secretion in SK-Hep-1 cell , 2010, Medical oncology.

[4]  Y. Minami,et al.  Cthrc1 selectively activates the planar cell polarity pathway of Wnt signaling by stabilizing the Wnt-receptor complex. , 2008, Developmental cell.

[5]  M. Fainzilber,et al.  Retrograde signaling in axonal regeneration , 2010, Experimental Neurology.

[6]  J. Chan,et al.  ErbB2 directly activates the exchange factor Dock7 to promote Schwann cell migration , 2008, The Journal of cell biology.

[7]  Yukinori Endo,et al.  A Rac switch regulates random versus directionally persistent cell migration , 2005, The Journal of cell biology.

[8]  L. Liaw,et al.  Collagen Triple Helix Repeat Containing 1, a Novel Secreted Protein in Injured and Diseased Arteries, Inhibits Collagen Expression and Promotes Cell Migration , 2005, Circulation research.

[9]  M. Jo,et al.  Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration* , 2010, The Journal of Biological Chemistry.

[10]  F. Castellino,et al.  Unexpected role of anticoagulant protein C in controlling epithelial barrier integrity and intestinal inflammation , 2011, Proceedings of the National Academy of Sciences.

[11]  Hua Su,et al.  MicroRNA-9 coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors. , 2010, Cell stem cell.

[12]  Shibi Lu,et al.  Expression changes and bioinformatic analysis of Wallerian degeneration after sciatic nerve injury in rat , 2013, Neuroscience Bulletin.

[13]  G. Nikkhah,et al.  Axonal Regeneration across Long Gaps in Silicone Chambers Filled with Schwann Cells Overexpressing High Molecular Weight FGF-2 , 2003, Cell transplantation.

[14]  Liduan Zheng,et al.  microRNA-9 Targets Matrix Metalloproteinase 14 to Inhibit Invasion, Metastasis, and Angiogenesis of Neuroblastoma Cells , 2012, Molecular Cancer Therapeutics.

[15]  H. Park,et al.  Rac1 GTPase controls myelination and demyelination , 2011, Bioarchitecture.

[16]  Keisuke Sawada,et al.  Autocrine regulation of TGF-&bgr;1-induced cell migration by exocytosis of ATP and activation of P2 receptors in human lung cancer cells , 2012, Journal of Cell Science.

[17]  Yingqun Wang,et al.  Wnt/Planar cell polarity signaling: A new paradigm for cancer therapy , 2009, Molecular Cancer Therapeutics.

[18]  D. Geschwind,et al.  Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. , 2011, The Journal of clinical investigation.

[19]  Rakesh Nagarajan,et al.  MicroRNAs Modulate Schwann Cell Response to Nerve Injury by Reinforcing Transcriptional Silencing of Dedifferentiation-Related Genes , 2011, The Journal of Neuroscience.

[20]  Xiaosong Gu,et al.  Construction of tissue engineered nerve grafts and their application in peripheral nerve regeneration , 2011, Progress in Neurobiology.

[21]  A. Lloyd,et al.  EphB Signaling Directs Peripheral Nerve Regeneration through Sox2-Dependent Schwann Cell Sorting , 2010, Cell.

[22]  C. Burge,et al.  Most mammalian mRNAs are conserved targets of microRNAs. , 2008, Genome research.

[23]  J. Ghislain,et al.  Control of myelination in Schwann cells: a Krox20 cis‐regulatory element integrates Oct6, Brn2 and Sox10 activities , 2006, EMBO reports.

[24]  Jingde Zhu,et al.  CTHRC1 is upregulated by promoter demethylation and transforming growth factor‐β1 and may be associated with metastasis in human gastric cancer , 2012, Cancer science.

[25]  C. Stigloher,et al.  MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary , 2008, Nature Neuroscience.

[26]  Kenneth M. Yamada,et al.  Random versus directionally persistent cell migration , 2009, Nature Reviews Molecular Cell Biology.

[27]  L. Wrabetz,et al.  MicroRNA-Deficient Schwann Cells Display Congenital Hypomyelination , 2010, The Journal of Neuroscience.

[28]  E. Shooter,et al.  Ras activation of a Rac1 exchange factor, Tiam1, mediates neurotrophin-3-induced Schwann cell migration. , 2005 .

[29]  E. Feldman,et al.  IGF-I promotes Schwann cell motility and survival via activation of Akt , 2000, Molecular and Cellular Endocrinology.

[30]  Guohui Ding,et al.  miR-221 and miR-222 promote Schwann cell proliferation and migration by targeting LASS2 after sciatic nerve injury , 2012, Journal of Cell Science.

[31]  L. Liaw,et al.  Cthrc1, a Novel Circulating Hormone Regulating Metabolism , 2012, PloS one.

[32]  Ueli Suter,et al.  Dicer in Schwann Cells Is Required for Myelination and Axonal Integrity , 2010, The Journal of Neuroscience.

[33]  M. Bennett,et al.  Connexin 32 increases the proliferative response of Schwann cells to neuregulin-1 (Nrg1) , 2009, Proceedings of the National Academy of Sciences.

[34]  M. Martinka,et al.  Aberrant Expression of Collagen Triple Helix Repeat Containing 1 in Human Solid Cancers , 2006, Clinical Cancer Research.

[35]  M. Schumacher,et al.  Wnt/β-Catenin Signaling Is an Essential and Direct Driver of Myelin Gene Expression and Myelinogenesis , 2011, The Journal of Neuroscience.

[36]  W. Talbot,et al.  erbb3 and erbb2 Are Essential for Schwann Cell Migration and Myelination in Zebrafish , 2005, Current Biology.

[37]  Songlin Zhou,et al.  Early changes of microRNAs expression in the dorsal root ganglia following rat sciatic nerve transection , 2011, Neuroscience Letters.

[38]  J. Delgado-García,et al.  Motoneuron adaptability to new motor tasks following two types of facial-facial anastomosis in cats. , 2003, Brain : a journal of neurology.

[39]  W. Guo,et al.  MicroRNA‐9 up‐regulates E‐cadherin through inhibition of NF‐κB1–Snail1 pathway in melanoma , 2012, The Journal of pathology.

[40]  R. Ketting,et al.  The role of small non-coding RNAs in genome stability and chromatin organization , 2010, Journal of Cell Science.

[41]  A. Gaultier,et al.  The Hemopexin Domain of Matrix Metalloproteinase-9 Activates Cell Signaling and Promotes Migration of Schwann Cells by Binding to Low-Density Lipoprotein Receptor-Related Protein , 2008, The Journal of Neuroscience.

[42]  I. Graef,et al.  Calcineurin/NFAT Signaling Is Required for Neuregulin-Regulated Schwann Cell Differentiation , 2009, Science.

[43]  S. S. Koh,et al.  Collagen triple helix repeat containing-1 promotes pancreatic cancer progression by regulating migration and adhesion of tumor cells. , 2013, Carcinogenesis.

[44]  R. Midha,et al.  Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. , 1998, The Journal of trauma.

[45]  K. Nave,et al.  Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development , 2007, The Journal of cell biology.

[46]  U. Suter,et al.  The function of RhoGTPases in axon ensheathment and myelination , 2008, Glia.

[47]  Guohui Ding,et al.  Profile of MicroRNAs following Rat Sciatic Nerve Injury by Deep Sequencing: Implication for Mechanisms of Nerve Regeneration , 2011, PloS one.