Efficient Remyelination Requires DNA Methylation

Sarah Moyon, Dan Ma, Jimmy L. Huynh, David J.c. Coutts, Chao Zhao, Patrizia Casaccia, Robin J.m. Franklin

Research output: Contribution to journalArticle

Abstract

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 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 OPCs and for DNMT3A in adult OPCs.
Original languageEnglish
Article numberENEURO.0336-16.2017
JournaleNeuro
Volume4
Issue number2
DOIs
Publication statusPublished - 20 Mar 2017

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Oligodendroglia
DNA Methylation
Methyltransferases
Stem Cells
DNA
Spinal Cord
Lysophosphatidylcholines
Myelin Sheath
Demyelinating Diseases
Transgenic Mice
Cell Differentiation
Central Nervous System
Injections

Bibliographical note

Copyright © 2017 Moyon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is
properly attributed

Keywords

  • Adult oligodendrocyte progenitor cells; DNA methylation; remyelination

Cite this

Moyon, S., Ma, D., Huynh, J. L., Coutts, D. J. C., Zhao, C., Casaccia, P., & Franklin, R. J. M. (2017). Efficient Remyelination Requires DNA Methylation. eNeuro, 4(2), [ENEURO.0336-16.2017]. https://doi.org/10.1523/ENEURO.0336-16.2017
Moyon, Sarah ; Ma, Dan ; Huynh, Jimmy L. ; Coutts, David J.c. ; Zhao, Chao ; Casaccia, Patrizia ; Franklin, Robin J.m. / Efficient Remyelination Requires DNA Methylation. In: eNeuro. 2017 ; Vol. 4, No. 2.
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Moyon, S, Ma, D, Huynh, JL, Coutts, DJC, Zhao, C, Casaccia, P & Franklin, RJM 2017, 'Efficient Remyelination Requires DNA Methylation', eNeuro, vol. 4, no. 2, ENEURO.0336-16.2017. https://doi.org/10.1523/ENEURO.0336-16.2017

Efficient Remyelination Requires DNA Methylation. / Moyon, Sarah; Ma, Dan; Huynh, Jimmy L.; Coutts, David J.c.; Zhao, Chao; Casaccia, Patrizia; Franklin, Robin J.m.

In: eNeuro, Vol. 4, No. 2, ENEURO.0336-16.2017, 20.03.2017.

Research output: Contribution to journalArticle

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AU - Coutts, David J.c.

AU - Zhao, Chao

AU - Casaccia, Patrizia

AU - Franklin, Robin J.m.

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N2 - 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 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 OPCs and for DNMT3A in adult OPCs.

AB - 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 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 OPCs and for DNMT3A in adult OPCs.

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Moyon S, Ma D, Huynh JL, Coutts DJC, Zhao C, Casaccia P et al. Efficient Remyelination Requires DNA Methylation. eNeuro. 2017 Mar 20;4(2). ENEURO.0336-16.2017. https://doi.org/10.1523/ENEURO.0336-16.2017