title: Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS.
abstract: Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an inducible conditional knock-out strategy to investigate whether continued oligodendrocyte expression of the recently identified transcription factor myelin gene regulatory factor (MRF) is required to maintain the integrity of myelin in the adult CNS. Genetic ablation of MRF in mature oligodendrocytes within the adult CNS resulted in a delayed but severe CNS demyelination, with clinical symptoms beginning at 5 weeks and peaking at 8 weeks after ablation of MRF. This demyelination was accompanied by microglial/macrophage infiltration and axonal damage. Transcripts for myelin genes, such as proteolipid protein, MAG, MBP, and myelin oligodendrocyte glycoprotein, were rapidly downregulated after ablation of MRF, indicating an ongoing requirement for MRF in the expression of these genes. Subsequently, a proportion of the recombined oligodendrocytes undergo apoptosis over a period of weeks. Surviving oligodendrocytes gradually lose the expression of mature markers such as CC1 antigen and their association with myelin, without reexpressing oligodendrocyte progenitor markers or reentering the cell cycle. These results demonstrate that ongoing expression of MRF within the adult CNS is critical to maintain mature oligodendrocyte identity and the integrity of CNS myelin.
authors.affiliation: Department of Anatomy and Neuroscience and the Centre for Neuroscience Research, The University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Koenning
authors.forename: Stacey
authors.initials: S
authors.lastname: Jackson
authors.forename: Curtis M
authors.initials: CM
authors.lastname: Hay
authors.forename: Clare
authors.initials: C
authors.lastname: Faux
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.forename: Melanie
authors.initials: M
authors.lastname: Willingham
authors.forename: Ben
authors.initials: B
authors.lastname: Emery
mesh_terms: D000367:Age Factors; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D014157:Transcription Factors; C571125:myelin gene regulatory factor, mouse