A network of genes is recruited in developing oligodendrocytes to coordinate the production of myelin, a deficiency of which can drastically impair neuronal function in the central nervous system. Mechanisms operative in regulating myelin gene expression can be revealed by defining the set of transcription factors and signaling pathways that are selectively and temporally activated in developing oligodendrocytes. To examine the changing pattern of transcription factors and other genes selectively expressed by developing oligodendrocytes, we established a reliable microarray system combined with purification of oligodendrocytes by flow cytometry at different stages of differentiation (Nielsen et al., 2006). Such an approach has enabled the isolation and profiling of a novel, non-myelinating population of oligodendrocytes. The function and regulation of several genes expressed by this population of non-myelinating oligodendrocytes is being further examined in transgenic models to identify the molecular basis for the switch from a non-myelinating to a myelinating phenotype. In addition to profiling messenger RNAs (mRNAs) with microarray technology, we examined microRNAs (miRNAs), a class of small non-coding RNAs with a roles in post-transcriptional regulation. We are defining those miRNA candidates that may regulate oligodendrocyte specification, proliferation and differentiation by conferring an additional level of selectivity to the gene expression program. Of the genes that are dynamically regulated during oligodendrocyte development, we selected several novel proteins for functional characterization (Nielsen et al., 2006). Together with this discovery-driven approach to identifying genes relevant for oligodendrocyte development, we continued our long-term study on the mechanism by which the zinc finger transcription factor Myt1 regulates neural gene transcription. Myt1 was found to interact with a transcriptional co-repressor, Sin3, that may locally modify chromatin structure to regulate myelin gene transcription (Romm et al., 2005). Finally, combining transcriptomics with in vivo demyelinating paradigms, we evaluated the expression profile following myelin loss. These studies form the basis for devising strategies to promote remyelination in diseases such as multiple sclerosis, Pelizaeus-Merzbacher disease and spinal cord injury by stimulating endogenous oligodendrocyte progenitors to proliferate, migrate and myelinate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002528-25
Application #
7322998
Study Section
(LDN)
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2006
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Hudson, Lynn D; Romm, Elena; Berndt, Jo Ann et al. (2011) A tool for examining the role of the zinc finger myelin transcription factor 1 (Myt1) in neural development: Myt1 knock-in mice. Transgenic Res 20:951-61
Szuchet, Sara; Nielsen, Joseph A; Lovas, Gabor et al. (2011) The genetic signature of perineuronal oligodendrocytes reveals their unique phenotype. Eur J Neurosci 34:1906-22
Nielsen, Joseph A; Lau, Pierre; Maric, Dragan et al. (2009) Integrating microRNA and mRNA expression profiles of neuronal progenitors to identify regulatory networks underlying the onset of cortical neurogenesis. BMC Neurosci 10:98
Lau, Pierre; Verrier, Jonathan D; Nielsen, Joseph A et al. (2008) Identification of dynamically regulated microRNA and mRNA networks in developing oligodendrocytes. J Neurosci 28:11720-30
Nielsen, Joseph A; Maric, Dragan; Lau, Pierre et al. (2006) Identification of a novel oligodendrocyte cell adhesion protein using gene expression profiling. J Neurosci 26:9881-91
Kim, Hyunsook; Barton, Elisabeth; Muja, Naser et al. (2005) Intact insulin and insulin-like growth factor-I receptor signaling is required for growth hormone effects on skeletal muscle growth and function in vivo. Endocrinology 146:1772-9
Romm, Elena; Nielsen, Joseph A; Kim, Jin G et al. (2005) Myt1 family recruits histone deacetylase to regulate neural transcription. J Neurochem 93:1444-53
Muja, Naser; Lovas, Gabor; Romm, Elena et al. (2004) Expression of a catalytically inactive transmembrane protein tyrosine phosphatase epsilon (tm-PTP epsilon) delays optic nerve myelination. Glia 48:278-97
Nielsen, Joseph A; Berndt, Jo Ann; Hudson, Lynn D et al. (2004) Myelin transcription factor 1 (Myt1) modulates the proliferation and differentiation of oligodendrocyte lineage cells. Mol Cell Neurosci 25:111-23
Hudson, Lynn D (2003) Pelizaeus-Merzbacher disease and spastic paraplegia type 2: two faces of myelin loss from mutations in the same gene. J Child Neurol 18:616-24

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