Antagonistic regulation of PAF1C and p-TEFb is required for oligodendrocyte differentiation.
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 (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-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 dal(knu6) 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.
Graduate School of Medicine, Korea University, Ansan, Gyeonggido 425-707, Republic of Korea.
Suhyun
S
Kim
Jun-Dae
JD
Kim
Ah-Young
AY
Chung
Hyung-Seok
HS
Kim
Young-Seop
YS
Kim
Myoung-Jin
MJ
Kim
Soonil
S
Koun
You Mie
YM
Lee
Myungchull
M
Rhee
Hae-Chul
HC
Park
Tae-Lin
TL
Huh
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques / Q000379:methods; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D002352:Carrier Proteins; C548894:Leo1 protein, zebrafish; D009687:Nuclear Proteins; D029961:Zebrafish Proteins; D042925:Positive Transcriptional Elongation Factor B