Dicer Ablation In Oligodendrocytes Impairs Oligodendrogenesis And Functional Recovery After Stroke

Introduction: Stroke-induced oligodendrogenesis contributes to ischemic brain remodeling and spontaneous functional recovery. Genes that regulate microRNA biogenesis in stroke-induced oligodendrogenesis remain little known. Methods: We employed a transgenic mouse line with conditional and inducible ablation of Dicer, a key gene of miRNA biogenesis, in myelin proteolipid protein (PLP) lineage oligodendrocytes (Dicer-KO). A PLP reporter mouse line was used as a control. Mice were subjected to transient (60min) middle cerebral artery occlusion (MCAO, n=8/group). An array of behavioral and cognitive tests were performed. All mice were sacrificed at 28 days after MCAO. Fluorescence-activated cell sorting (FACS) in combination with miRNA sequencing were used to profile the miRNA alteration. Results: Compared to ischemic reporter mice, ischemic Dicer-KO mice exhibited significantly increased infarct volumes and significantly impaired neurological outcomes and cognitive deficits post stroke as assayed by social recognition memory, novel object recognition, and Morris water-maze tests. Immunochemistry analysis revealed that ischemic Dicer-KO mice showed a significant reduction of the number of PLP-lineage NG2 + oligodendrocyte precursor cells (OPCs) and APC + myelinating oligodendrocytes compared to ischemic reporter mice. Moreover, Dicer-KO mice exhibited a robust reduction of myelinated axons measured by myelin binding protein (MBP) and Bielschowsky/Luxol Fast Blue assay. FACS analysis of PLP-lineage cells in peri-infarct regions showed that ablation of Dicer significantly decreased many miRNAs including the miR-200 family that are known to regulate oligodendrogenesis. Conclusion: Our data indicate that Dicer in PLP lineage oligodendrocytes is required for stroke-induced oligodendrogenesis and myelination, and that Dicer is involved in spontaneous functional recovery after stroke.