Antagonistic regulation of PAF1C and p-TEFb is required for oligodendrocyte differentiation

Suhyun Kim, Jun Dae Kim, Ah Young Chung, Hyung Seok Kim, Young Seop Kim, Myoung Jin Kim, Soonil Koun, You Mie Lee, Myungchull Rhee, Hae Chul Park, Tae Lin Huh

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8 Citations (Scopus)

Abstract

Oligodendrocytes are myelinating glial cells in the CNS and are essential for proper neuronal function. During development, oligodendrocyte progenitor cells (OPCs) are specified from the motor neuron precursor domain of the ventral spinal cord and differentiate into myelinating oligodendrocytes after migration to the white matter of the neural tube. Cell cycle control of OPCs influences the balance between immature OPCs and myelinating oligodendrocytes, but the precise mechanism regulating the differentiation of OPCs into myelinating oligodendrocytes is unclear. To understand the mechanisms underlying oligodendrocyte differentiation, an N-ethyl-Nnitrosourea- based mutagenesis screen was performed and a zebrafish leo1 mutant, dalmuri (dal knu6) was identified in the current study. Leo1 is a component of the evolutionarily conserved RNA polymerase II-associated factor 1 complex (PAF1C), which is a positive regulator of transcription elongation. The dal knu6 mutant embryos specified motor neurons and OPCs normally, and at the appropriate time, but OPCs subsequently failed to differentiate into myelinating oligodendrocytes and were eliminated by apoptosis. A loss-offunction study of cdc73, another member of PAF1C, showed the same phenotype in the CNS, indicating that PAF1C function is required for oligodendrocyte differentiation. Interestingly, inhibition of positive transcription elongation factor b (p-TEFb), rescued downregulated gene expression and impaired oligodendrocyte differentiation in the dal knu6 mutant and Cdc73-deficient embryos. Together, these results indicate that antagonistic regulation of gene expression byPAF1Cand p-TEFb plays a crucial role in oligodendrocyte development in the CNS.

Original languageEnglish
Pages (from-to)8201-8207
Number of pages7
JournalJournal of Neuroscience
Volume32
Issue number24
DOIs
Publication statusPublished - 2012 Jun 13

ASJC Scopus subject areas

  • Neuroscience(all)

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    Kim, S., Kim, J. D., Chung, A. Y., Kim, H. S., Kim, Y. S., Kim, M. J., Koun, S., Lee, Y. M., Rhee, M., Park, H. C., & Huh, T. L. (2012). Antagonistic regulation of PAF1C and p-TEFb is required for oligodendrocyte differentiation. Journal of Neuroscience, 32(24), 8201-8207. https://doi.org/10.1523/JNEUROSCI.5344-11.2012