Oligodendrocyte progenitor cells (OPC) are the principal source of new myelin in the central nervous system and 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 OPC into myelinating oligodendrocytes (OL). However, it remains to be determined whether DNA methylation is also critical for the differentiation of adult OPC 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 OL. To functionally assess the role of DNMT1 and DNMT3 in adult OPC, we used mice with inducible and lineage-specific ablation of Dnmt3a and/or Dnmt1 (i.e., Plp-creER(t);Dnmt3a-flox, Plp-creER(t);Dnmt1-flox, Plp-creER(t);Dnmt1-flox;Dnmt3a-flox). Upon lysolecithin injection in the spinal cord of these transgenic mice, we detected defective OPC differentiation and inefficient remyelination in the Dnmt3a null and Dnmt1/Dnmt3a null mice, but not in the Dnmt1 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 OPC and for DNMT3A in adult OPC.
Significance Statement The regenerative therapy of enhancing remyelination is the subject of much current investigation for a number of central nervous system disorders. However, its mechanisms remain incompletely understood. A recent study identified a distinct role of the DNA methyltransferase 1 (DNMT1) in developmental myelination; here we report a dominant role for DNMT3A in adult remyelination after lysolecithin-induced demyelination. Overall this is of high relevance as it indicates that neonatal and adult oligodendrocyte progenitor cells might be characterized by distinct epigenetic landscapes that may need to be taken into consideration for the development of future therapeutic strategies.
The authors declare no competing financial interests.
NIH [NIH-R37NS42925-14]; UK Multiple Sclerosis Society
↵* S.M. and D.M. are Co-first authors