Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.
Ann Neurol. 2009 Dec;66(6):843-57. doi: 10.1002/ana.21927.
MicroRNAs (miRNAs) regulate gene expression and have many roles in the brain, but a role in oligodendrocyte (OL) function has not been demonstrated.
A Dicer floxed conditional allele was crossed with the proteolipid protein promoter-driven inducible Cre allele to generate inducible, OL-specific Dicer-floxed mice.
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.
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.
MicroRNAs（miRNAs）调节基因表达，在大脑中具有多种功能，但尚未证明其在少突胶质细胞（OL）功能中的作用。
将 Dicer floxed 条件性等位基因与髓鞘碱性蛋白启动子驱动的诱导型 Cre 等位基因杂交，以产生诱导型、OL 特异性 Dicer-floxed 小鼠。
OL 特异性 Dicer 突变体在大脑中表现出脱髓鞘、氧化损伤、炎症性星形胶质细胞和小胶质细胞增生，最终导致神经元变性和寿命缩短。miR-219 及其靶基因 ELOVL7（长链脂肪酸延长蛋白 7）被鉴定为参与这些小鼠表型发育的主要分子成分。ELOVL7 的过表达导致脂质积累，而 miR-219 的共过表达则抑制了这种积累。在 Dicer 突变体大脑中，富含髓鞘的脑区积累了过多的脂质，而过氧化物酶体β-氧化活性显著降低。
成熟 OL 中 Dicer 的后天性缺失会导致脱髓鞘、脂质积累、过氧化物酶体和氧化损伤增加，从而导致炎症性神经元变性，表明 miRNAs 在维持成熟 OL 中的脂质和氧化还原平衡中发挥着重要作用，这对于支持轴突完整性以及形成紧密髓鞘是必要的。
