Dicer Deletion in Astrocytes Inhibits Oligodendroglial Differentiation and Myelination

Increasing evidence has shown that astrocytes are implicated in regulating oligodendrocyte myelination,but the underlying mechanisms remain largely unknown.To understand whether microRNAs in astrocytes function in regulating oligodendroglial differentiation and myelination in the developing and adult CNS,we generated inducible astrocyte-specific Dicer conditional knockout mice(hGFAP-CreERT;Dicer fl/fl).By using a reporter mouse line(mT/mG),we confirmed that hGFAP-CreERT drives an efficient and astrocyte-specific recombination in the developing CNS,upon tamoxifen treatment from postnatal day 3(P3)to P7.The Dicer deletion in astrocytes resulted in inhibited oligodendroglial differentiation and myelination in the developing CNS of Dicer cKO mice at P10 and P14,and did not alter the densities of neurons or axons,indicating that Dicer in astrocytes is required for oligodendrocyte myelination.Consequently,the Dicer deletion in astrocytes at P3 resulted in impaired spatial memory and motor coordination at the age of 9 weeks.To understand whether Dicer in astrocytes is also required for remyelination,we induced Dicer deletion in 3-month-old mice and then injected lysolecithin into the corpus callosum to induce demyelination.The Dicer deletion in astrocytes blocked remyelination in the corpus callosum 14 days after induced demyelination.Together,our results indicate that Dicer in astrocytes is required for oligodendroglia myelination in both the developing and adult CNS.

Chronic Exposure to Hypoxia Inhibits Myelinogenesis and Causes Motor Coordination Deficits in Adult Mice

Exposure to chronic hypoxia is considered to be a risk factor for deficits in brain function in adults,but the underlying mechanisms remain largely unknown.Since active myelinogenesis persists in the adult central nervous system,here we aimed to investigate the impact of chronic hypoxia on myelination and the related functional consequences in adult mice.Using a transgenic approach to label newly-generated myelin sheaths(NG2-CreER^(TM);Tau-mGFP),we found that myelinogenesis was highly active in most brain regions,such as the motor cortex and corpus callosum.After exposure to hypoxia(10%oxygen)12 h per day for 4 weeks,myelinogenesis was largely inhibited in the 4-month old brain and the mice displayed motor coordination deficits revealed by the beam-walking test.To determine the relationship between the inhibited myelination and functional impairment,we induced oligoden-droglia-specific deletion of the transcription factor 01ig2 by tamoxifen(NG2-CreER^(TM);Tau-mGFP;Olig2 fl/fl)in adult mice to mimic the decreased myelinogenesis caused by hypoxia.The deletion of OHg2 inhibited myelinogenesis and consequently impaired motor coordination,suggesting that myelinogenesis is required for motor function in adult mice.To understand whether enhancing myelination could protect brain functions against hypoxia,we treated hypoxic mice with the myelination-enhancing drug-clemastine,which resulted in enhanced myelogenesis and improved motor coordination.Taken together,our data indicate that chronic hypoxia inhibits myelinogenesis and causes functional deficits in the brain and that enhancing myelinogenesis protects brain functions against hypoxia-related deficits.