Dicer Deletion in Astrocytes Inhibits Oligodendroglial Differentiation and Myelination

Abstract

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.

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