SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients

NEUROBIOLOGY OF DISEASE

卷:77

Article

Haenisch, Sierk^1,2  Zhao, Yi³  Chhibber, Aparna¹  Kaiboriboon, Kitti⁴  Do, Lynn V.^5,6  Vogelgesang, Silke⁷  Barbaro, Nicholas M.⁸  Alldredge, Brian K.^6,9  Lowenstein, Daniel H.⁹  Cascorbi, Ingolf²  Kroetz, Deanna L.¹ 

[1] Univ Calif San Francisco, Sch Pharm, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[2] Univ Hosp Schleswig Holstein, Inst Expt & Clin Pharmacol, D-24105 Kiel, Germany

[3] Univ Hosp Schleswig Holstein, Dept Nucl Med Mol Imaging & Therapy, D-24105 Kiel, Germany

[4] Swedish Epilepsy Ctr, Inst Neurosci, Seattle, WA USA

[5] Univ Calif San Francisco, Med Ctr, Clin Pharm Serv, San Francisco, CA USA

[6] Univ Calif San Francisco, Sch Pharm, Dept Clin Pharm, San Francisco, CA 94143 USA

[7] Ernst Moritz Arndt Univ Greifswald, Inst Pathol, Dept Neuropathol, Greifswald, Germany

[8] Indiana Univ, Sch Med, Dept Neurol Surg & Neurol, Indianapolis, IN USA

[9] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA USA

关键词: MicroRNA;    SOX11;    miR-212-3p;    miR-132-3p;    hsa-miR-34c-5p;    GABA;    Glutamate;    Neurogenesis;    Neuronal differentiation;    Epilepsy;    Temporal lobe;   

DOI  :  10.1016/j.nbd.2015.02.025

来源: Elsevier

【 摘 要 】

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally control the expression of their target genes via RNA interference. There is increasing evidence that expression of miRNAs is dysregulated in neuronal disorders, including epilepsy, a chronic neurological disorder characterized by spontaneous recurrent seizures. Mesial temporal lobe epilepsy (MILE) is a common type of focal epilepsy in which disease-induced abnormalities of hippocampal neurogenesis in the subgranular zone as well as gliosis and neuronal cell loss in the cornu ammonis area are reported. We hypothesized that in MILE altered miRNA-mediated regulation of target genes could be involved in hippocampal cell remodeling. A miRNA screen was performed in hippocampal focal and non-focal brain tissue samples obtained from the temporal neocortex (both n = 8) of MILE patients. Out of 215 detected miRNAs, two were differentially expressed (hsa-miR-34c-5p: mean increase of 5.7 fold (p = 0.014), hsa-miR-212-3p: mean decrease of 76.9% (p = 0.0014)). After in-silico target gene analysis and filtering, reporter gene assays confirmed RNA interference for hsa-miR-34c-5p with 3'-UTR sequences of GABRA3, GRM7 and GABBR2 and for hsa-miR-212-3p with 3'-UTR sequences of SOX11. MECP2, ADCY1 and ABCG2. Reporter gene assays with mutated 3'-UTR sequences of the transcription factor SOX11 identified two different binding sites for hsa-miR-212-3p and its primary transcript partner hsa-miR-132-3p. Additionally, there was an inverse time-dependent expression of Sox11 and miR-212-3p as well as miR-132-3p in rat neonatal cortical neurons. Transfection of neurons with anti-miRs for miR-212-3p and miR-132-3p suggest that both miRNAs work synergistically to control Sox11 expression. Taken together, these results suggest that differential miRNA expression in neurons could contribute to an altered function of the transcription factor SOX11 and other genes in the setting of epilepsy, resulting not only in impaired neural differentiation, but also in imbalanced neuronal excitability and accelerated drug export. (C) 2015 Elsevier Inc. All rights reserved.

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