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.
Highlights
Astrocytes are a type of glial cell that are widely distributed in the central nervous system (CNS) [1]
To examine the recombination specificity and efficiency driven by hGFAP-CreERT, we crossed this line to the mT(omato)/ mG(FP) reporter line and mice were treated with tamoxifen at postnatal day 3 (P3) and sacrificed at P14 (Fig. 1A)
To verify if the hGFAP-CreERT line can induce astrocyte-specific recombination in the postnatal CNS, we carried out immunostaining for GFAP, brain lipid-binding protein (BLBP, astrocytes), NeuN, CC1 (OLs), Iba1, and NG2 (OPCs) on the hGFAP-CreERT; mT/ mG brain sections (Fig. 1B–D)
Summary
Astrocytes are a type of glial cell that are widely distributed in the central nervous system (CNS) [1]. Oligodendrocytes (OLs) wrap axons and form myelin sheaths that ensure fast and efficient transmission of action potentials in the CNS [7, 8]. The OL differentiation and myelination are initiated by axon-OL recognition, and this process is guided by interacting with other cell types [9, 10]. Astrocytes are closely associated with OLs by communicating through gap junctions and secretory factors [11, 12]. In vitro evidence has shown that astrocytes can influence the differentiation, proliferation and migration of OL precursor cells (OPCs) [13]. Astrocytes secret growth factors that can promote OPC proliferation and survival in cultures [14]. Elimination of astrocyte in the developing CNS causes OL death and disrupts myelination in the developing CNS, indicating that astrocytes are functionally required for OL
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