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The Journal of Neuroscience, September 7, 2005, 25(36):8311-8321; doi:10.1523/JNEUROSCI.1850-05.2005

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Development/Plasticity/Repair
Combinatorial Profiles of Oligodendrocyte-Selective Classes of Transcriptional Regulators Differentially Modulate Myelin Basic Protein Gene Expression

Solen Gokhan,^1,2,3,7 * Mireya Marin-Husstege,^8 * Shau Yu Yung,⁴ Darah Fontanez,^8,9 Patrizia Casaccia-Bonnefil,^8,9 and Mark F. Mehler^{1,2,3,4,5,6,7}

¹Institute for Brain Disorders and Neural Regeneration, ²F. M. Kirby Program in Neural Protection and Repair, Departments of ³Neurology, ⁴Neuroscience, and ⁵Psychiatry and Behavioral Sciences, ⁶Einstein Cancer Center, and ⁷Rose F. Kennedy Center for Research in Mental Retardation and Developmental Disabilities, Albert Einstein College of Medicine, Bronx, New York 10461, and ⁸Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, and ⁹Undergraduate Research Program RISE at Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854

Recent studies suggest that specific neural basic helix-loop-helix (HLH; i.e., Olig1 and Olig2, Mash1), associated inhibitory HLH (i.e., Id2 and Id4), high-mobility group domain (i.e., Sox10), and homeodomain (i.e., Nkx2.2) transcription factors are involved in oligodendrocyte (OL) lineage specification and progressive stages of maturation including myelination. However, the developmental interplay among these lineage-selective determinants, in a cell- and maturational stage-specific context, has not yet been defined. We show here in vivo and in vitro developmental expression profiles for these distinct classes of transcriptional regulators of OLs. We show that progressive stages of OL lineage maturation are characterized by dynamic changes in the subcellular distribution of these transcription factors and by different permutations of combinatorial transcriptional codes. Transient transfections of these precise combinatorial codes with a luciferase reporter gene driven by the myelin basic protein promoter define how changes in the molecular composition of these transcriptional complexes modulate myelin gene expression. Our overall findings suggest that the dynamic interplay between developmental stage-specific classes of transcriptional activators and associated inhibitory factors orchestrate myelin gene expression during terminal maturation of the mammalian CNS.

Key words: neuronal–glial coupling; oligodendrocytes; lineage maturation; transcriptional regulation; forebrain; proneural genes

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Received March 24, 2004; revised July 22, 2005; accepted July 23, 2005.

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