Functional organization of an Mbp enhancer exposes striking transcriptional regulatory diversity within myelinating glia.
In mammals, large caliber axons are ensheathed by myelin, a glial specialization supporting axon integrity and conferring accelerated and energy-efficient action potential conduction. Myelin basic protein (MBP) is required for normal myelin elaboration with maximal mbp transcription in oligodendrocytes requiring the upstream M3 enhancer. To further characterize the mechanism regulating mbp transcription, we defined M3 structure/function relationships by evaluating its evolutionary conservation, DNA footprints and the developmental programing conferred in mice by M3 derivatives. Multiple M3 regulatory element combinations were found to drive expression in oligodendrocytes and Schwann cells with a minimal 129 bp sequence conferring expression in oligodendrocytes throughout myelin elaboration, maintenance and repair. Unexpectedly, M3 derivatives conferred markedly different spatial and temporal expression programs thus illuminating striking transcriptional heterogeneity within post-mitotic oligodendrocytes. Finally, one M3 derivative engaged only during primary myelination, not during adult remyelination, demonstrating that transcriptional regulation in the two states is not equivalent.
Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, Quebec, Canada.
Nancy
N
Dionne
Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, Quebec, Canada.
Samar
S
Dib
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Bente
B
Finsen
Institut National De La Santé Et De La Recherche Médicale, U836-GIN iRTSV-GPC, Site Santé La Tronche, BP170, Grenoble, Cedex 9, France.
Eric
E
Denarier
Institute of Neuropathology, University Hospital, Münster, Pottkamp 2, Münster, Germany.
Tanja
T
Kuhlmann
Division of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université De Sherbrooke, Sherbrooke, Quebec, Canada.
Régen
R
Drouin
Department of Medicine, McGill University/MUHC Research Institute, Montreal, Quebec, Canada.
Maia
M
Kokoeva
Ontario Institute for Cancer Research, MaRS Centre, South Tower, Toronto, Ontario, Canada.
Thomas J
TJ
Hudson
Department of Medicine, University of Toronto, Samuel Lunenfeld and Toronto General Research Institutes, Toronto, Ontario, Canada.|Department of Immunology and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Kathy
K
Siminovitch
Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, Quebec, Canada.
Hana C
HC
Friedman
Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, Quebec, Canada.
Alan C
AC
Peterson
D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D002645:Chickens; D017124:Conserved Sequence; D053263:Gene Regulatory Networks; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics* / Q000378:metabolism*; D009186:Myelin Sheath / Q000235:genetics* / Q000378:metabolism*; D009900:Optic Nerve / Q000254:growth & development / Q000378:metabolism; D012584:Sciatic Nerve / Q000254:growth & development / Q000378:metabolism; D016415:Sequence Alignment; D013116:Spinal Cord / Q000254:growth & development / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
D030161:Avian Proteins; C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D001616:beta-Galactosidase
Schwann cell; gene regulation; myelin; myelin repair; oligodendrocyte