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

Abstract

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.

In VivoAnalysis of Ascl1 Defined Progenitors Reveals Distinct Developmental Dynamics during Adult Neurogenesis and Gliogenesis

“…Ascl1 expression has been reported in OPCs in culture (Kondo and Raff, 2000;Wang et al, 2001;Gokhan et al, 2005), and forced expression of Ascl1 in neural progenitor cultures biases fate to neurons and oligodendrocytes, but not astrocytes (Gokhan et al, 2005;Sugimori et al, 2007). Lineage tracing of Ascl1 expressing cells in spinal neural tube development revealed these cells are fated to neurons and oligodendrocytes, but not astrocytes in vivo (Battiste et al, 2007).…”

Increased Citrullination of Histone H3 in Multiple Sclerosis Brain and Animal Models of Demyelination: A Role for Tumor Necrosis Factor-Induced Peptidylarginine Deiminase 4 Translocation

“…5C) (Gokhan et al, 2005), the localization of PAD4 was still mainly cytoplasmic, suggesting that nuclear translocation of the enzyme is not part of the constitutive differentiation program but may require exogenous signals. We considered the following.…”

“…Mechanism of translocation of PAD4 into the nucleus PAD4 expression was analyzed in a proliferating, undifferentiated, murine oligodendrocyte progenitor cell line, Oli-Neu (Scholze et al, 1996;Gokhan et al, 2005), to elucidate some of the factors involved in the translocation of PAD4. Immunofluorescence showed a predominantly cytoplasmic enzyme distribution and a small amount of nuclear labeling (Fig.…”

REST and CoREST are transcriptional and epigenetic regulators of seminal neural fate decisions

“…31 Dynamic changes in the deployment and redeployment of different combinations and permutations of transcription factors mediate downstream developmental programs, including terminal differentiation and neural network integration. 32 More recently, epigenetic mechanisms have emerged as an novel molecular interface for integrating cues from these diverse cell intrinsic, cell-cell associated and environmental signaling pathways and, in turn, for regulating the deployment of specific gene networks that determine neural cell identity. These developmental processes may be mediated through context-dependent gene activation, repression, long-term silencing, graded and coordinate gene expression, establishment of epigenetic memory states and dynamic changes in nuclear architecture.…”