Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, UK.
eNeuro. 2017 Mar 30;4(2). doi: 10.1523/ENEURO.0336-16.2017. eCollection 2017 Mar-Apr.
Oligodendrocyte progenitor cells (OPCs) are the principal source of new myelin in the central nervous system. A better understanding of how they mature into myelin-forming cells is of high relevance for remyelination. It has recently been demonstrated that during developmental myelination, the DNA methyltransferase 1 (DNMT1), but not DNMT3A, is critical for regulating proliferation and differentiation of OPCs into myelinating oligodendrocytes (OLs). However, it remains to be determined whether DNA methylation is also critical for the differentiation of adult OPCs during remyelination. After lysolecithin-induced demyelination in the ventrolateral spinal cord white matter of adult mice of either sex, we detected increased levels of DNA methylation and higher expression levels of the DNA methyltransferase DNMT3A and lower levels of DNMT1 in differentiating adult OLs. To functionally assess the role of DNMT1 and DNMT3 in adult OPCs, we used mice with inducible and lineage-specific ablation of and/or (i.e., , ). Upon lysolecithin injection in the spinal cord of these transgenic mice, we detected defective OPC differentiation and inefficient remyelination in the null and null mice, but not in the null mice. Taken together with previous results in the developing spinal cord, these data suggest an age-dependent role of distinct DNA methyltransferases in the oligodendrocyte lineage, with a dominant role for DNMT1 in neonatal OPCs and for DNMT3A in adult OPCs.
少突胶质前体细胞（OPC）是中枢神经系统中产生髓鞘的主要细胞。深入了解它们如何成熟为形成髓鞘的细胞对于髓鞘的再生具有重要意义。最近已经证明，在发育性髓鞘形成过程中，DNA 甲基转移酶 1（DNMT1）而非 DNMT3A 对于调节 OPC 增殖和分化为形成髓鞘的少突胶质细胞（OL）至关重要。然而，尚不确定 DNA 甲基化是否对于成年 OPC 在髓鞘再生过程中的分化也是至关重要的。在成年雌雄小鼠腹侧脊髓白质中用溶卵磷脂诱导脱髓鞘后，我们在分化的成年 OL 中检测到 DNA 甲基化水平升高，DNMT3A 的表达水平升高，而 DNMT1 的表达水平降低。为了在功能上评估 DNMT1 和 DNMT3 在成年 OPC 中的作用，我们使用了可诱导和谱系特异性敲除和/或（即， ）的小鼠。在这些转基因小鼠脊髓中注射溶卵磷脂后，我们在 缺失和 缺失小鼠中检测到 OPC 分化缺陷和髓鞘再生效率降低，但在 缺失小鼠中未检测到这种情况。这些数据与在发育中的脊髓中得到的先前结果相结合，表明不同的 DNA 甲基转移酶在少突胶质细胞谱系中具有年龄依赖性的作用，DNMT1 在新生 OPC 中起主导作用，而 DNMT3A 在成年 OPC 中起主导作用。
