Dicer ablation in oligodendrocytes provokes neuronal impairment in mice.
OBJECTIVE
MicroRNAs (miRNAs) regulate gene expression and have many roles in the brain, but a role in oligodendrocyte (OL) function has not been demonstrated.


METHODS
A Dicer floxed conditional allele was crossed with the proteolipid protein promoter-driven inducible Cre allele to generate inducible, OL-specific Dicer-floxed mice.


RESULTS
OL-specific Dicer mutants show demyelination, oxidative damage, inflammatory astrocytosis and microgliosis in the brain, and eventually neuronal degeneration and shorter lifespan. miR-219 and its target ELOVL7 (elongation of very long chain fatty acids protein 7) were identified as the main molecular components that are involved in the development of the phenotype in these mice. Overexpressing ELOVL7 results in lipid accumulation, which is suppressed by miR-219 co-overexpression. In Dicer mutant brain, excess lipids accumulate in myelin-rich brain regions, and the peroxisomal beta-oxidation activity is dramatically reduced.


CONCLUSIONS
Postnatal Dicer ablation in mature OLs results in inflammatory neuronal degeneration through increased demyelination, lipid accumulation, and peroxisomal and oxidative damage, and therefore indicates that miRNAs play an essential role in the maintenance of lipids and redox homeostasis in mature OLs that are necessary for supporting axonal integrity as well as the formation of compact myelin.
Shin
Daesung
D
Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.
Shin
Ji-Yeon
JY
McManus
Michael T
MT
Ptácek
Louis J
LJ
Fu
Ying-Hui
YH
D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000172:deficiency*; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D004722:Endoribonucleases / Q000172:deficiency*; D000081031:Fatty Acid Elongases; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000235:genetics; D020287:In Situ Nick-End Labeling / Q000379:methods; D019426:Integrases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043244:Ribonuclease III; D013629:Tamoxifen / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism
D000943:Antigens, Differentiation; D018931:Antineoplastic Agents, Hormonal; C000630963:Elovl7 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D035683:MicroRNAs; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C036763:monocyte-macrophage differentiation antigen; D013629:Tamoxifen; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; C045073:Cre recombinase; D019426:Integrases; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases