title: Functional requirement of dicer1 and miR-17-5p in reactive astrocyte proliferation after spinal cord injury in the mouse.
abstract: Reactive astrogliosis after spinal cord injury (SCI) contributes to glial scar formation that impedes axonal regeneration. The mechanisms underlying reactive astrocyte proliferation upon injury remain partially understood. MicroRNAs (miRNAs) function as a major class of post-transcriptional gene expression regulators that participate in many biological processes. However, miRNA function during reactive astrogliosis, particularly in injury-induced astrocyte proliferation, has not been carefully examined. In this study, we conditionally deleted Dicer1 gene encoding an enzyme that is required for mature miRNA generation, and examined the proliferative behavior of Dicer1-null reactive astrocytes in the transected mouse spinal cord. We found that injury-induced proliferation is blocked in Dicer1-null astrocytes. Previous reports indicate that miR-17-5p family members are upregulated during SCI. We therefore tested functional contribution of miR-17-5p to the proliferation of reactive astrocytes in vitro. Our results showed that a synthetic miR-17-5p mimic is able to rescue the proliferation defect of Dicer1-null astrocytes, while an antisense inhibitor of miR-17-5p blocked lipopolysaccharide-induced astrocytic proliferation. Similar results are also observed in leukemia inhibitory factor (LIF)-treated astroglial cultures suggesting that miR-17-5p particularly modulates reactive astrocyte proliferation initiated by LIF presumably via the JAK/STAT3 pathway. Furthermore, overexpression of miR-17-5p leads to decrease of several cell cycle regulators in cultured astroglia and astrocytoma cell line C6. Our conclusion is that miRNAs are indispensable to the injury-induced reactive astrocyte proliferation, and that miR-17-5p may be a major player regulating this pathological process by affecting cell cycle machinery.
authors.affiliation: West China Developmental & Stem Cell Institute, West China Second University Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
authors.forename: Peiwei
authors.initials: P
authors.lastname: Hong
authors.forename: Mei
authors.initials: M
authors.lastname: Jiang
authors.forename: Hedong
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D039481:CD11b Antigen; D053148:Caspase 3; D053487:DEAD-box RNA Helicases; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D053605:Leukemia Inhibitory Factor; D008070:Lipopolysaccharides; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D043244:Ribonuclease III; D001616:beta-Galactosidase; C543614:Mirn17 microRNA, mouse; C512773:Olig2 protein, mouse; C509781:Dicer1 protein, mouse
keywords: Dicer (Dicer1); miR-17-5p; miRNAs; proliferation; spinal cord injury