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., and Huh, T.L. (2012) Antagonistic Regulation of PAF1C and p-TEFb Is Required for Oligodendrocyte Differentiation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 32(24):8201-8207.
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-N-nitrosourea-based mutagenesis screen was performed and a zebrafish leo1 mutant, dalmuri (dalknu6) 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 dalknu6 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-of-function 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 dalknu6 mutant and Cdc73-deficient embryos. Together, these results indicate that antagonistic regulation of gene expression by PAF1C
and p-TEFb plays a crucial role in oligodendrocyte development in the CNS.