||MicroRNA-145 and -212 regulate astrocytic function after spinal cord injury
||Department of Life Sciences
Spinal cord injury
脊髓損傷後，星狀膠細胞進行大量增生(astrogliosis)以促進神經組織修復，這些星狀膠細胞會幫助與保護神經細胞，並形成膠質疤(glial scar)將受傷處包圍住以防止二次傷害擴散。最近研究發現微型核糖核酸(microRNA)在神經退化疾病與創傷中扮演重要的角色。本研究發現在神經細胞與星狀膠細胞高度表現之microRNA ─ mir-145，在脊髓損傷後一周與一個月的時間點表現量顯著下降。利用細胞實驗發現，給予細菌脂多醣(lipopolysaccharide)誘發發炎訊號，會透過p38 MAPK與ERK1/2訊息傳遞路徑抑制星狀膠細胞中mir-145之表現量。動物實驗則利用慢病毒(lentivirus)轉染脊髓組織，藉GFAP啟動子專一地將mir-145大量表現於星狀膠細胞(其為高度表現GFAP之細胞)。在脊髓損傷位置周圍，高度表現mir-145之星狀膠細胞的數量明顯少於控制組，細胞纖維密度也較低，導致活化之微膠細胞擴散。以細胞實驗觀察，高度表現mir-145之星狀膠細胞的體積降低、延伸觸腳數目變少、生長速度降低、細胞遷移能力也變弱。利用冷光分析實驗(3’-UTR luciferase reporter analysis)與西方點墨法(western blot)確認GFAP與c-myc為mir-145之目標mRNA，推測mir-145可能分別藉由抑制GFAP與c-myc之表現進而影響細胞型態與生長。另外發現星狀膠質細胞麩胺酸轉送蛋白GLAST亦為mir-145之目標mRNA。另一方面，實驗結果顯示在脊髓損傷或星狀膠細胞處理LPS後，mir-212之表現量也下降。而過度表現mir-212會改變星狀膠細胞形態的現象，其可能藉由透過抑制β-actin之表現與組成。綜合以上結果發現，mir-145與mir-212會調控星狀膠細胞的動態表現(dynamics)；推測mir-145與mir-212表現下降為脊髓損傷後星狀膠細胞增生與細胞形態變化的重要影響因子。
Astrogliosis is essential for tissue repair after spinal cord injury (SCI), since astrocytes play supporting roles for neurons and form glial scar as a physical barrier to prohibit the expansion of secondary injury. Deregulated microRNAs (miRNAs) have been reported to contribute to CNS neurodegeneration and damages. In this study, we present that mir-145, a miRNA species enriched in rat neurons and astrocytes, was downregulated at the lesion site at 1 week (subacute) and 1 month (chronic) after SCI. The in vitro studies showed that potent inflammagen lipopolysaccharide (LPS) inhibited astrocytic mir-145 expression via p38 MAPK or ERK1/2 pathway. We used lentivirus-mediated pre-miRNA delivery system using the promoter of glial fibrillary acidic protein (GFAP), an astrocyte-specific intermediate filament, to induce astrocyte-specific overexpression of mir-145 at the lesion site. The results indicated that astrocytic mir-145 overexpression attenuated the pileup of astrocytes at the lesion border and reduced their process density, along with the increased accumulation of activated microglia. In parallel, overexpression of mir-145 reduced astrocytic cell size and the number of astrocytic cell processes. Astrocytic cell proliferation and migration were diminished after mir-145 overexpression. Through 3’-UTR luciferase reporter assay and western blot analysis, we identified that GFAP and c-Myc were the direct targets of mir-145 in astrocytes. These findings demonstrate that mir-145 regulates astrocytic dynamics partly via the downregulation of GFAP and c-Myc. In addition, we identified that astrocytic glutamate transporter, GLAST, was one of mir-145 targets.
In the regard to mir-212, the miRNA was observed to be expressed in neurons mainly, but in astrocytes and oligodendrocytes to some degree. Its level was also reduced at the lesion site after SCI. After exposure of astrocytes to LPS, astrocytic mir-212 was downregulated. Overexpression of mir-212 caused the morphological change of astrocytes into elongated process-bearing shapes, which might be due to mir-212 induced repression of β-actin expression.
Together, the results from the study as described above point to the novel role of mir-145 and mir-212 in the regulation of astrocytic dynamics. Moreover, the findings reveal that the downregulation of mir-145 and mir-212 in astrocytes after SCI might be critical for astrogliosis after SCI.
Abbreviation list X
Spinal cord and neural cells 2
Spinal cord injury 3
Mir-145 and mir-212-related studies 12
Specific aims 14
Materials and Methods 15
Spinal cord injury 16
Intraspinal injection of lentivirus particles 16
In situ hybridization combined with immunohistochemistry 17
Cell culture preparation 18
Quantitative real-time polymerase chain reaction 19
Lentivirus-mediated overexpression of mir-145 and mir-212 19
Transfection of mir-145 mimics and antagomir-145 20
Cell scratch injury 21
MTT cell viability assay 21
Cell proliferation assay 21
Cell motility 22
Transwell migration assay 22
Western blot analysis 23
Quantification of GFAP+ or Iba1+ cells in the injured spinal cord 23
Measurement of the length and number of astrocytic processes 24
3’-UTR luciferase reporter assay 24
Statistical Analysis 25
Spatial expression pattern of mir-145 in adult rat spinal cord 27
Expression of mir-145 in distinct spinal cell types 27
Reduced expression of mir-145 in the injured spinal cord 28
Downregulation of mir-145 expression in astrocytes by inflammatory stimuli 28
Regulation of mir-145 expression in astrocytes by p38 MAPK and ERK1/2 signaling pathways 29
Hypertrophy is attenuated in astrocytes with mir-145 overexpression 30
Glial scar suppressed by mir-145 overexpression 30
Regulation of astrocytic dynamics by mir-145 31
GFAP is one of mir-145 targets 32
C-Myc is one validated target of mir-145 34
Mir-212 expression in adult spinal cord 35
SCI-induced downregulation of mir-212 36
Mir-145 in SCI-associated astrogliosis 39
Mir-145 targets 42
Mir-212 in neural function 43
Inflammation regulation of Mir-145 and mir-212 44
Astrogliosis in tissue repair 44
Astrocytes in brain and spinal cord 45
Potential function of mir-212 in oligodendrocytes 46
Abe Y, Yamamoto T, Sugiyama Y, Watanabe T, Saito N, Kayama H, Kumagai T (1999) Apoptotic cells associated with Wallerian degeneration after experimental spinal cord injury: a possible mechanism of oligodendroglial death. J Neurotrauma 16:945-952.
Adammek M, Greve B, Kassens N, Schneider C, Bruggemann K, Schuring AN, Starzinski-Powitz A, Kiesel L, Gotte M (2013) MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of an in vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors. Fertil Steril 99:1346-1355 e1345.
Agostini M, Tucci P, Steinert JR, Shalom-Feuerstein R, Rouleau M, Aberdam D, Forsythe ID, Young KW, Ventura A, Concepcion CP, Han YC, Candi E, Knight RA, Mak TW, Melino G (2011) microRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proc Natl Acad Sci U S A 108:21099-21104.
Allison DJ, Ditor DS (2015) Immune dysfunction and chronic inflammation following spinal cord injury. Spinal Cord 53:14-18.
Anderson MA, Ao Y, Sofroniew MV (2014) Heterogeneity of reactive astrocytes. Neurosci Lett 565:23-29.
Annunziato L, Cataldi M, Pignataro G, Secondo A, Molinaro P (2007) Glutamate-independent calcium toxicity: introduction. Stroke 38:661-664.
Bali P, Kenny PJ (2013) MicroRNAs and Drug Addiction. Front Genet 4:43.
Bareyre FM, Schwab ME (2003) Inflammation, degeneration and regeneration in the injured spinal cord: insights from DNA microarrays. Trends Neurosci 26:555-563.
Beschorner R, Dietz K, Schauer N, Mittelbronn M, Schluesener HJ, Trautmann K, Meyermann R, Simon P (2007) Expression of EAAT1 reflects a possible neuroprotective function of reactive astrocytes and activated microglia following human traumatic brain injury. Histol Histopathol 22:515-526.
Bhalala OG, Srikanth M, Kessler JA (2013) The emerging roles of microRNAs in CNS injuries. Nat Rev Neurol 9:328-339.
Bhalala OG, Pan L, Sahni V, McGuire TL, Gruner K, Tourtellotte WG, Kessler JA (2012) microRNA-21 regulates astrocytic response following spinal cord injury. J Neurosci 32:17935-17947.
Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S (2009) MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 324:1710-1713.
Boucher JM, Peterson SM, Urs S, Zhang C, Liaw L (2011) The miR-143/145 cluster is a novel transcriptional target of Jagged-1/Notch signaling in vascular smooth muscle cells. J Biol Chem 286:28312-28321.
Bradbury EJ, Carter LM (2011) Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 84:306-316.
Campos-Melo D, Droppelmann CA, He Z, Volkening K, Strong MJ (2013) Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain 6:26.
Chen Z, Zeng H, Guo Y, Liu P, Pan H, Deng A, Hu J (2010) miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc. J Exp Clin Cancer Res 29:151.
Chiyomaru T, Tatarano S, Kawakami K, Enokida H, Yoshino H, Nohata N, Fuse M, Seki N, Nakagawa M (2011) SWAP70, actin-binding protein, function as an oncogene targeting tumor-suppressive miR-145 in prostate cancer. Prostate.
Cho WC, Chow AS, Au JS (2011) MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1. RNA Biol 8:125-131.
Clark AK, Old EA, Malcangio M (2013) Neuropathic pain and cytokines: current perspectives. J Pain Res 6:803-814.
Coleman MP, Perry VH (2002) Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532-537.
Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J (2014) Functional regeneration beyond the glial scar. Exp Neurol 253:197-207.
Cui JG, Li YY, Zhao Y, Bhattacharjee S, Lukiw WJ (2010) Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease. J Biol Chem 285:38951-38960.
Darian-Smith C (2009) Synaptic plasticity, neurogenesis, and functional recovery after spinal cord injury. Neuroscientist 15:149-165.
David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:388-399.
David S, Lopez-Vales R, Wee Yong V (2012) Harmful and beneficial effects of inflammation after spinal cord injury: potential therapeutic implications. Handb Clin Neurol 109:485-502.
Davis EJ, Foster TD, Thomas WE (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34:73-78.
De Pietri Tonelli D, Clovis YM, Huttner WB (2014) Detection and monitoring of microRNA expression in developing mouse brain and fixed brain cryosections. Methods Mol Biol 1092:31-42.
Deumens R, Koopmans GC, Joosten EA (2005) Regeneration of descending axon tracts after spinal cord injury. Prog Neurobiol 77:57-89.
Dharap A, Vemuganti R (2010) Ischemic pre-conditioning alters cerebral microRNAs that are upstream to neuroprotective signaling pathways. J Neurochem 113:1685-1691.
Dharap A, Bowen K, Place R, Li LC, Vemuganti R (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 29:675-687.
Di Giovanni S, Knoblach SM, Brandoli C, Aden SA, Hoffman EP, Faden AI (2003) Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Ann Neurol 53:454-468.
Di Y, Lei Y, Yu F, Changfeng F, Song W, Xuming M (2014) MicroRNAs expression and function in cerebral ischemia reperfusion injury. J Mol Neurosci 53:242-250.
Ding Q, Wu Z, Guo Y, Zhao C, Jia Y, Kong F, Chen B, Wang H, Xiong S, Que H, Jing S, Liu S (2006) Proteome analysis of up-regulated proteins in the rat spinal cord induced by transection injury. Proteomics 6:505-518.
Duchossoy Y, Arnaud S, Feldblum S (2001) Matrix metalloproteinases: potential therapeutic target in spinal cord injury. Clin Chem Lab Med 39:362-367.
Dugas JC, Cuellar TL, Scholze A, Ason B, Ibrahim A, Emery B, Zamanian JL, Foo LC, McManus MT, Barres BA (2010) Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron 65:597-611.
Enciu AM, Popescu BO, Gheorghisan-Galateanu A (2012) MicroRNAs in brain development and degeneration. Mol Biol Rep 39:2243-2252.
Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969-2000). Neurochem Res 25:1439-1451.
Fang KM, Lin TC, Chan TC, Ma SZ, Tzou BC, Chang WR, Liu JJ, Chiou SH, Yang CS, Tzeng SF (2013) Enhanced cell growth and tumorigenicity of rat glioma cells by stable expression of human CD133 through multiple molecular actions. Glia 61:1402-1417.
Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143-2155.
Ferrer I, Blanco R (2000) N-myc and c-myc expression in Alzheimer disease, Huntington disease and Parkinson disease. Brain Res Mol Brain Res 77:270-276.
Filbin MT (2003) Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 4:703-713.
Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54:1-18.
Garg N, Po A, Miele E, Campese AF, Begalli F, Silvano M, Infante P, Capalbo C, De Smaele E, Canettieri G, Di Marcotullio L, Screpanti I, Ferretti E, Gulino A (2013) microRNA-17-92 cluster is a direct Nanog target and controls neural stem cell through Trp53inp1. EMBO J 32:2819-2832.
Godoy J, Nishimura M, Webster NJ (2011) Gonadotropin-releasing hormone induces miR-132 and miR-212 to regulate cellular morphology and migration in immortalized LbetaT2 pituitary gonadotrope cells. Mol Endocrinol 25:810-820.
Goodall EF, Heath PR, Bandmann O, Kirby J, Shaw PJ (2013) Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front Cell Neurosci 7:178.
Gris D, Marsh DR, Oatway MA, Chen Y, Hamilton EF, Dekaban GA, Weaver LC (2004) Transient blockade of the CD11d/CD18 integrin reduces secondary damage after spinal cord injury, improving sensory, autonomic, and motor function. J Neurosci 24:4043-4051.
Hagg T, Oudega M (2006) Degenerative and spontaneous regenerative processes after spinal cord injury. J Neurotrauma 23:264-280.
Haramati S, Chapnik E, Sztainberg Y, Eilam R, Zwang R, Gershoni N, McGlinn E, Heiser PW, Wills AM, Wirguin I, Rubin LL, Misawa H, Tabin CJ, Brown R, Jr., Chen A, Hornstein E (2010) miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 107:13111-13116.
He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522-531.
Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, Kauppinen S, Delacourte A, De Strooper B (2008) Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A 105:6415-6420.
Heman-Ackah SM, Hallegger M, Rao MS, Wood MJ (2013) RISC in PD: the impact of microRNAs in Parkinson's disease cellular and molecular pathogenesis. Front Mol Neurosci 6:40.
Hildebrand C, Remahl S, Persson H, Bjartmar C (1993) Myelinated nerve fibres in the CNS. Prog Neurobiol 40:319-384.
Hollander JA, Im HI, Amelio AL, Kocerha J, Bali P, Lu Q, Willoughby D, Wahlestedt C, Conkright MD, Kenny PJ (2010) Striatal microRNA controls cocaine intake through CREB signalling. Nature 466:197-202.
Hsu JY, McKeon R, Goussev S, Werb Z, Lee JU, Trivedi A, Noble-Haeusslein LJ (2006) Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J Neurosci 26:9841-9850.
Hu JG, Lu HZ, Wang YX, Bao MS, Zhao BM, Zhou JS (2010) BMP signaling mediates astrocyte differentiation of oligodendrocyte progenitor cells. Tohoku J Exp Med 222:195-200.
Huang WC, Kuo WC, Cherng JH, Hsu SH, Chen PR, Huang SH, Huang MC, Liu JC, Cheng H (2006) Chondroitinase ABC promotes axonal re-growth and behavior recovery in spinal cord injury. Biochem Biophys Res Commun 349:963-968.
Hutchison ER, Kawamoto EM, Taub DD, Lal A, Abdelmohsen K, Zhang Y, Wood WH, 3rd, Lehrmann E, Camandola S, Becker KG, Gorospe M, Mattson MP (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61:1018-1028.
Iliopoulos D, Hirsch HA, Struhl K (2009) An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 139:693-706.
Im HI, Hollander JA, Bali P, Kenny PJ (2010) MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat Neurosci 13:1120-1127.
Incoronato M, Garofalo M, Urso L, Romano G, Quintavalle C, Zanca C, Iaboni M, Nuovo G, Croce CM, Condorelli G (2010) miR-212 increases tumor necrosis factor-related apoptosis-inducing ligand sensitivity in non-small cell lung cancer by targeting the antiapoptotic protein PED. Cancer Res 70:3638-3646.
Iyer A, Zurolo E, Prabowo A, Fluiter K, Spliet WG, van Rijen PC, Gorter JA, Aronica E (2012) MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One 7:e44789.
Jee MK, Jung JS, Im YB, Jung SJ, Kang SK (2012) Silencing of miR20a is crucial for Ngn1-mediated neuroprotection in injured spinal cord. Hum Gene Ther 23:508-520.
Jeyaseelan K, Lim KY, Armugam A (2008) MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke 39:959-966.
Jia Z, Zhu H, Li J, Wang X, Misra H, Li Y (2012) Oxidative stress in spinal cord injury and antioxidant-based intervention. Spinal Cord 50:264-274.
Jiang S, Yu R, Mao B, Gao L (2000) [An experimental study on traumatic brain injury for inducing neuronal apoptosis in rats]. Hua Xi Yi Ke Da Xue Xue Bao 31:358-361.
Jones TB, McDaniel EE, Popovich PG (2005) Inflammatory-mediated injury and repair in the traumatically injured spinal cord. Curr Pharm Des 11:1223-1236.
Kang SK, So HH, Moon YS, Kim CH (2006) Proteomic analysis of injured spinal cord tissue proteins using 2-DE and MALDI-TOF MS. Proteomics 6:2797-2812.
Karimi-Abdolrezaee S, Billakanti R (2012) Reactive astrogliosis after spinal cord injury-beneficial and detrimental effects. Mol Neurobiol 46:251-264.
Kawahara Y (2010) [Implications of microRNA dysfunction in the pathogenesis of ALS]. Rinsho Shinkeigaku 50:979-981.
Kigerl KA, Popovich PG (2009) Toll-like receptors in spinal cord injury. Curr Top Microbiol Immunol 336:121-136.
Kigerl KA, de Rivero Vaccari JP, Dietrich WD, Popovich PG, Keane RW (2014) Pattern recognition receptors and central nervous system repair. Exp Neurol 258:5-16.
Kim DH, Yeo SH, Park JM, Choi JY, Lee TH, Park SY, Ock MS, Eo J, Kim HS, Cha HJ (2014) Genetic markers for diagnosis and pathogenesis of Alzheimer's disease. Gene 545:185-193.
Kimelberg HK (2010) Functions of mature mammalian astrocytes: a current view. Neuroscientist 16:79-106.
Korn T, Magnus T, Jung S (2005) Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GLAST: a mechanism mediated by tumor necrosis factor-alpha. FASEB J 19:1878-1880.
Koutsis G, Siasos G, Spengos K (2013) The emerging role of microRNA in stroke. Curr Top Med Chem 13:1573-1588.
Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312-318.
Kumru H, Kofler M, Valls-Sole J, Portell E, Vidal J (2009) Brainstem reflexes are enhanced following severe spinal cord injury and reduced by continuous intrathecal baclofen. Neurorehabil Neural Repair 23:921-927.
Kumru H, Vidal J, Kofler M, Portell E, Valls-Sole J (2010) Alterations in excitatory and inhibitory brainstem interneuronal circuits after severe spinal cord injury. J Neurotrauma 27:721-728.
Lau P, Sala Frigerio C, De Strooper B (2014) Variance in the identification of microRNAs deregulated in Alzheimer's disease and possible role of lincRNAs in the pathology: The need of larger datasets. Ageing Res Rev 17C:43-53.
Lee H, Lee S, Cho IH, Lee SJ (2013) Toll-like receptors: sensor molecules for detecting damage to the nervous system. Curr Protein Pept Sci 14:33-42.
Lee HC, Chen CY, Au LC (2011a) Systemic comparison of repression activity for miRNA and siRNA associated with different types of target sequences. Biochem Biophys Res Commun 411:393-396.
Lee SK, Teng Y, Wong HK, Ng TK, Huang L, Lei P, Choy KW, Liu Y, Zhang M, Lam DS, Yam GH, Pang CP (2011b) MicroRNA-145 regulates human corneal epithelial differentiation. PLoS One 6:e21249.
Lee ST, Chu K, Im WS, Yoon HJ, Im JY, Park JE, Park KH, Jung KH, Lee SK, Kim M, Roh JK (2011c) Altered microRNA regulation in Huntington's disease models. Exp Neurol 227:172-179.
Li JS, Yao ZX (2012) MicroRNAs: novel regulators of oligodendrocyte differentiation and potential therapeutic targets in demyelination-related diseases. Mol Neurobiol 45:200-212.
Li X, Jin P (2010) Roles of small regulatory RNAs in determining neuronal identity. Nat Rev Neurosci 11:329-338.
Li YY, Cui JG, Dua P, Pogue AI, Bhattacharjee S, Lukiw WJ (2011) Differential expression of miRNA-146a-regulated inflammatory genes in human primary neural, astroglial and microglial cells. Neurosci Lett 499:109-113.
Liang ZQ, Wang XX, Wang Y, Chuang DM, DiFiglia M, Chase TN, Qin ZH (2005) Susceptibility of striatal neurons to excitotoxic injury correlates with basal levels of Bcl-2 and the induction of P53 and c-Myc immunoreactivity. Neurobiol Dis 20:562-573.
Lin ST, Fu YH (2009) miR-23 regulation of lamin B1 is crucial for oligodendrocyte development and myelination. Dis Model Mech 2:178-188.
Liu CL, Jin AM, Tong BH (2003) Detection of gene expression pattern in the early stage after spinal cord injury by gene chip. Chin J Traumatol 6:18-22.
Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, Turner RJ, Jickling G, Sharp FR (2010) Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab 30:92-101.
Liu NK, Xu XM (2011) MicroRNA in central nervous system trauma and degenerative disorders. Physiol Genomics 43:571-580.
Liu NK, Wang XF, Lu QB, Xu XM (2009) Altered microRNA expression following traumatic spinal cord injury. Exp Neurol 219:424-429.
Liu Y, Chen Q, Song Y, Lai L, Wang J, Yu H, Cao X, Wang Q (2011) MicroRNA-98 negatively regulates IL-10 production and endotoxin tolerance in macrophages after LPS stimulation. FEBS Lett 585:1963-1968.
Liu YP, Yang CS, Tzeng SF (2008) Inhibitory regulation of glutamate aspartate transporter (GLAST) expression in astrocytes by cadmium-induced calcium influx. J Neurochem 105:137-150.
Lu WH, Wang CY, Chen PS, Wang JW, Chuang DM, Yang CS, Tzeng SF (2013) Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia. J Neurosci Res 91:694-705.
Ma L, Wei L, Wu F, Hu Z, Liu Z, Yuan W (2013) Advances with microRNAs in Parkinson's disease research. Drug Des Devel Ther 7:1103-1113.
Maciotta S, Meregalli M, Torrente Y (2013) The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci 7:265.
Magill ST, Cambronne XA, Luikart BW, Lioy DT, Leighton BH, Westbrook GL, Mandel G, Goodman RH (2010) microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc Natl Acad Sci U S A 107:20382-20387.
Marino RJ, Barros T, Biering-Sorensen F, Burns SP, Donovan WH, Graves DE, Haak M, Hudson LM, Priebe MM (2003) International standards for neurological classification of spinal cord injury. J Spinal Cord Med 26 Suppl 1:S50-56.
Martin SE, Caplen NJ (2006) Mismatched siRNAs downregulate mRNAs as a function of target site location. FEBS Lett 580:3694-3698.
Mense SM, Sengupta A, Zhou M, Lan C, Bentsman G, Volsky DJ, Zhang L (2006) Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes. Physiol Genomics 25:435-449.
Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ (2003) Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 1:882-891.
Mocchetti I, Wrathall JR (1995) Neurotrophic factors in central nervous system trauma. J Neurotrauma 12:853-870.
Montalban E, Mattugini N, Ciarapica R, Provenzano C, Savino M, Scagnoli F, Prosperini G, Carissimi C, Fulci V, Matrone C, Calissano P, Nasi S (2014) MiR-21 is an Ngf-modulated microRNA that supports Ngf signaling and regulates neuronal degeneration in PC12 cells. Neuromolecular Med 16:415-430.
Mor E, Cabilly Y, Goldshmit Y, Zalts H, Modai S, Edry L, Elroy-Stein O, Shomron N (2011) Species-specific microRNA roles elucidated following astrocyte activation. Nucleic Acids Res 39:3710-3723.
Mouradian MM (2012) MicroRNAs in Parkinson's disease. Neurobiol Dis 46:279-284.
Mujtaba T, Piper DR, Kalyani A, Groves AK, Lucero MT, Rao MS (1999) Lineage-restricted neural precursors can be isolated from both the mouse neural tube and cultured ES cells. Dev Biol 214:113-127.
Nahid MA, Yao B, Dominguez-Gutierrez PR, Kesavalu L, Satoh M, Chan EK (2013) Regulation of TLR2-mediated tolerance and cross-tolerance through IRAK4 modulation by miR-132 and miR-212. J Immunol 190:1250-1263.
Nakahama T, Hanieh H, Nguyen NT, Chinen I, Ripley B, Millrine D, Lee S, Nyati KK, Dubey PK, Chowdhury K, Kawahara Y, Kishimoto T (2013) Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. Proc Natl Acad Sci U S A 110:11964-11969.
Nakanishi K, Nakasa T, Tanaka N, Ishikawa M, Yamada K, Yamasaki K, Kamei N, Izumi B, Adachi N, Miyaki S, Asahara H, Ochi M (2010) Responses of microRNAs 124a and 223 following spinal cord injury in mice. Spinal Cord 48:192-196.
Nashmi R, Fehlings MG (2001) Mechanisms of axonal dysfunction after spinal cord injury: with an emphasis on the role of voltage-gated potassium channels. Brain Res Brain Res Rev 38:165-191.
Nieto-Diaz M, Esteban FJ, Reigada D, Munoz-Galdeano T, Yunta M, Caballero-Lopez M, Navarro-Ruiz R, Del Aguila A, Maza RM (2014) MicroRNA dysregulation in spinal cord injury: causes, consequences and therapeutics. Front Cell Neurosci 8:53.
Noguchi S, Mori T, Hoshino Y, Yamada N, Nakagawa T, Sasaki N, Akao Y, Maruo K (2011) Comparative Study of Anti-Oncogenic MicroRNA-145 in Canine and Human Malignant Melanoma. J Vet Med Sci.
Oberheim NA, Goldman SA, Nedergaard M (2012) Heterogeneity of astrocytic form and function. Methods Mol Biol 814:23-45.
Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, Yamane J, Yoshimura A, Iwamoto Y, Toyama Y, Okano H (2006) Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med 12:829-834.
Olson L (2002) Medicine: clearing a path for nerve growth. Nature 416:589-590.
Omran A, Ashhab MU, Gan N, Kong H, Peng J, Yin F (2013) Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-alpha , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture. ScientificWorldJournal 2013:208309.
Ostenfeld MS, Bramsen JB, Lamy P, Villadsen SB, Fristrup N, Sorensen KD, Ulhoi B, Borre M, Kjems J, Dyrskjot L, Orntoft TF (2010) miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors. Oncogene 29:1073-1084.
Park JK, Henry JC, Jiang J, Esau C, Gusev Y, Lerner MR, Postier RG, Brackett DJ, Schmittgen TD (2011) miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor. Biochem Biophys Res Commun 406:518-523.
Pastor MD, Garcia-Yebenes I, Fradejas N, Perez-Ortiz JM, Mora-Lee S, Tranque P, Moro MA, Pende M, Calvo S (2009) mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J Biol Chem 284:22067-22078.
Pekny M, Pekna M (2004) Astrocyte intermediate filaments in CNS pathologies and regeneration. J Pathol 204:428-437.
Pekny M, Eliasson C, Chien CL, Kindblom LG, Liem R, Hamberger A, Betsholtz C (1998) GFAP-deficient astrocytes are capable of stellation in vitro when cocultured with neurons and exhibit a reduced amount of intermediate filaments and an increased cell saturation density. Exp Cell Res 239:332-343.
Pernet V, Schwab ME (2012) The role of Nogo-A in axonal plasticity, regrowth and repair. Cell Tissue Res 349:97-104.
Pizzi MA, Crowe MJ (2006) Transplantation of fibroblasts that overexpress matrix metalloproteinase-3 into the site of spinal cord injury in rats. J Neurotrauma 23:1750-1765.
Pogue AI, Cui JG, Li YY, Zhao Y, Culicchia F, Lukiw WJ (2010) Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neurosci Lett 476:18-22.
Priestley JV, Michael-Titus AT, Tetzlaff W (2012) Limiting spinal cord injury by pharmacological intervention. Handb Clin Neurol 109:463-484.
Rasband MN, Trimmer JS, Schwarz TL, Levinson SR, Ellisman MH, Schachner M, Shrager P (1998) Potassium channel distribution, clustering, and function in remyelinating rat axons. J Neurosci 18:36-47.
Remenyi J, Hunter CJ, Cole C, Ando H, Impey S, Monk CE, Martin KJ, Barton GJ, Hutvagner G, Arthur JS (2010) Regulation of the miR-212/132 locus by MSK1 and CREB in response to neurotrophins. Biochem J 428:281-291.
Remenyi J, van den Bosch MW, Palygin O, Mistry RB, McKenzie C, Macdonald A, Hutvagner G, Arthur JS, Frenguelli BG, Pankratov Y (2013) miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity. PLoS One 8:e62509.
Ryan KM, O'Donovan SM, McLoughlin DM (2013) Electroconvulsive stimulation alters levels of BDNF-associated microRNAs. Neurosci Lett 549:125-129.
Sachdeva M, Mo YY (2010) miR-145-mediated suppression of cell growth, invasion and metastasis. Am J Transl Res 2:170-180.
Sandhir R, Gregory E, Berman NE (2014) Differential response of miRNA-21 and its targets after traumatic brain injury in aging mice. Neurochem Int 78:117-121.
Saugstad JA (2010) MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J Cereb Blood Flow Metab 30:1564-1576.
Schonrock N, Gotz J (2012) Decoding the non-coding RNAs in Alzheimer's disease. Cell Mol Life Sci 69:3543-3559.
Schwab ME (2004) Nogo and axon regeneration. Curr Opin Neurobiol 14:118-124.
Seeds N, Mikesell S, Vest R, Bugge T, Schaller K, Minor K (2011) Plasminogen activator promotes recovery following spinal cord injury. Cell Mol Neurobiol 31:961-967.
Sellers DL, Maris DO, Horner PJ (2009) Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci 29:6722-6733.
Shao Y, Qu Y, Dang S, Yao B, Ji M (2013) MiR-145 inhibits oral squamous cell carcinoma (OSCC) cell growth by targeting c-Myc and Cdk6. Cancer Cell Int 13:51.
Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, Ghosh B (2009) Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc Natl Acad Sci U S A 106:5761-5766.
Shenoy A, Blelloch RH (2014) Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nat Rev Mol Cell Biol 15:565-576.
Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146-156.
Sjolund BH (2002) Pain and rehabilitation after spinal cord injury: the case of sensory spasticity? Brain Res Brain Res Rev 40:250-256.
Skaper SD, Argentini C, Barbierato M (2012) Culture of neonatal rodent microglia, astrocytes, and oligodendrocytes from cortex and spinal cord. Methods Mol Biol 846:67-77.
Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG (2005) Regulation of miRNA expression during neural cell specification. Eur J Neurosci 21:1469-1477.
Soderblom C, Luo X, Blumenthal E, Bray E, Lyapichev K, Ramos J, Krishnan V, Lai-Hsu C, Park KK, Tsoulfas P, Lee JK (2013) Perivascular fibroblasts form the fibrotic scar after contusive spinal cord injury. J Neurosci 33:13882-13887.
Strickland ER, Hook MA, Balaraman S, Huie JR, Grau JW, Miranda RC (2011) MicroRNA dysregulation following spinal cord contusion: implications for neural plasticity and repair. Neuroscience 186:146-160.
Su W, Hopkins S, Nesser NK, Sopher B, Silvestroni A, Ammanuel S, Jayadev S, Moller T, Weinstein J, Garden GA (2014) The p53 transcription factor modulates microglia behavior through microRNA-dependent regulation of c-Maf. J Immunol 192:358-366.
Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17:1-14.
Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335-376.
Thompson CD, Zurko JC, Hanna BF, Hellenbrand DJ, Hanna A (2013) The therapeutic role of interleukin-10 after spinal cord injury. J Neurotrauma 30:1311-1324.
Thuret S, Moon LD, Gage FH (2006) Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 7:628-643.
Van den Hove DL, Kompotis K, Lardenoije R, Kenis G, Mill J, Steinbusch HW, Lesch KP, Fitzsimons CP, De Strooper B, Rutten BP (2014) Epigenetically regulated microRNAs in Alzheimer's disease. Neurobiol Aging 35:731-745.
Volvert ML, Rogister F, Moonen G, Malgrange B, Nguyen L (2012) MicroRNAs tune cerebral cortical neurogenesis. Cell Death Differ 19:1573-1581.
Wada R, Akiyama Y, Hashimoto Y, Fukamachi H, Yuasa Y (2010) miR-212 is downregulated and suppresses methyl-CpG-binding protein MeCP2 in human gastric cancer. Int J Cancer 127:1106-1114.
Walmsley AR, Mir AK (2007) Targeting the Nogo-A signalling pathway to promote recovery following acute CNS injury. Curr Pharm Des 13:2470-2484.
Wanet A, Tacheny A, Arnould T, Renard P (2012) miR-212/132 expression and functions: within and beyond the neuronal compartment. Nucleic Acids Res 40:4742-4753.
Wang CY, Chen JK, Wu YT, Tsai MJ, Shyue SK, Yang CS, Tzeng SF (2011a) Reduction in antioxidant enzyme expression and sustained inflammation enhance tissue damage in the subacute phase of spinal cord contusive injury. J Biomed Sci 18:13.
Wang WX, Huang Q, Hu Y, Stromberg AJ, Nelson PT (2011b) Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter. Acta Neuropathol 121:193-205.
Wang WX, Wilfred BR, Baldwin DA, Isett RB, Ren N, Stromberg A, Nelson PT (2008) Focus on RNA isolation: obtaining RNA for microRNA (miRNA) expression profiling analyses of neural tissue. Biochim Biophys Acta 1779:749-757.
Weidner N, Ner A, Salimi N, Tuszynski MH (2001) Spontaneous corticospinal axonal plasticity and functional recovery after adult central nervous system injury. Proc Natl Acad Sci U S A 98:3513-3518.
Weigelt K, Bergink V, Burgerhout KM, Pescatori M, Wijkhuijs A, Drexhage HA (2013) Down-regulation of inflammation-protective microRNAs 146a and 212 in monocytes of patients with postpartum psychosis. Brain Behav Immun 29:147-155.
White RE, Jakeman LB (2008) Don't fence me in: harnessing the beneficial roles of astrocytes for spinal cord repair. Restor Neurol Neurosci 26:197-214.
Witwer KW, Sisk JM, Gama L, Clements JE (2010) MicroRNA regulation of IFN-beta protein expression: rapid and sensitive modulation of the innate immune response. J Immunol 184:2369-2376.
Wong HK, Veremeyko T, Patel N, Lemere CA, Walsh DM, Esau C, Vanderburg C, Krichevsky AM (2013) De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Hum Mol Genet 22:3077-3092.
Xu C, Zhang Y, Zheng H, Loh HH, Law PY (2014) Morphine modulates mouse hippocampal progenitor cell lineages by up-regulating miR-181a level. Stem Cells.
Xu Q, Liu LZ, Qian X, Chen Q, Jiang Y, Li D, Lai L, Jiang BH (2011) MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res.
Xu Q, Liu LZ, Qian X, Chen Q, Jiang Y, Li D, Lai L, Jiang BH (2012) MiR-145 directly targets p70S6K1 in cancer cells to inhibit tumor growth and angiogenesis. Nucleic Acids Res 40:761-774.
Yamaguchi S, Yamahara K, Homma K, Suzuki S, Fujii S, Morizane R, Monkawa T, Matsuzaki Y, Kangawa K, Itoh H (2011) The role of microRNA-145 in human embryonic stem cell differentiation into vascular cells. Atherosclerosis 219:468-474.
Yang B, Guo H, Zhang Y, Chen L, Ying D, Dong S (2011) MicroRNA-145 regulates chondrogenic differentiation of mesenchymal stem cells by targeting Sox9. PLoS One 6:e21679.
Yin R, Zhang S, Wu Y, Fan X, Jiang F, Zhang Z, Feng D, Guo X, Xu L (2011) microRNA-145 suppresses lung adenocarcinoma-initiating cell proliferation by targeting OCT4. Oncol Rep 25:1747-1754.
Yin Y, Yan ZP, Lu NN, Xu Q, He J, Qian X, Yu J, Guan X, Jiang BH, Liu LZ (2013) Downregulation of miR-145 associated with cancer progression and VEGF transcriptional activation by targeting N-RAS and IRS1. Biochim Biophys Acta 1829:239-247.
Yu JY, Chung KH, Deo M, Thompson RC, Turner DL (2008) MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Exp Cell Res 314:2618-2633.
Yu YM, Gibbs KM, Davila J, Campbell N, Sung S, Todorova TI, Otsuka S, Sabaawy HE, Hart RP, Schachner M (2011) MicroRNA miR-133b is essential for functional recovery after spinal cord injury in adult zebrafish. Eur J Neurosci 33:1587-1597.
Yunta M, Nieto-Diaz M, Esteban FJ, Caballero-Lopez M, Navarro-Ruiz R, Reigada D, Pita-Thomas DW, del Aguila A, Munoz-Galdeano T, Maza RM (2012) MicroRNA dysregulation in the spinal cord following traumatic injury. PLoS One 7:e34534.
Zhang HY, Zheng SJ, Zhao JH, Zhao W, Zheng LF, Zhao D, Li JM, Zhang XF, Chen ZB, Yi XN (2011) MicroRNAs 144, 145, and 214 are down-regulated in primary neurons responding to sciatic nerve transection. Brain Res 1383:62-70.
Zhang J, Guo H, Qian G, Ge S, Ji H, Hu X, Chen W (2010) MiR-145, a new regulator of the DNA fragmentation factor-45 (DFF45)-mediated apoptotic network. Mol Cancer 9:211.
Zhang J, Wang L, Li B, Huo M, Mu M, Liu J, Han J (2014) miR-145 downregulates the expression of cyclin-dependent kinase 6 in human cervical carcinoma cells. Exp Ther Med 8:591-594.
Zhang N, Yin Y, Xu SJ, Wu YP, Chen WS (2012) Inflammation & apoptosis in spinal cord injury. Indian J Med Res 135:287-296.
Zhang W, Potrovita I, Tarabin V, Herrmann O, Beer V, Weih F, Schneider A, Schwaninger M (2005) Neuronal activation of NF-kappaB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab 25:30-40.
Zhou X, He X, Ren Y (2014) Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regen Res 9:1787-1795.
Ziu M, Fletcher L, Rana S, Jimenez DF, Digicaylioglu M (2011) Temporal differences in microRNA expression patterns in astrocytes and neurons after ischemic injury. PLoS One 6:e14724.