HDAC1 and HDAC2 regulate oligodendrocyte differentiation by disrupting the beta-catenin-TCF interaction.
Oligodendrocyte development is regulated by the interaction of repressors and activators in a complex transcriptional network. We found that two histone-modifying enzymes, HDAC1 and HDAC2, were required for oligodendrocyte formation. Genetic deletion of both Hdac1 and Hdac2 in oligodendrocyte lineage cells resulted in stabilization and nuclear translocation of beta-catenin, which negatively regulates oligodendrocyte development by repressing Olig2 expression. We further identified the oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of beta-catenin for regulating oligodendrocyte differentiation. Targeted disruption of Tcf7l2 in mice led to severe defects in oligodendrocyte maturation, whereas expression of its dominant-repressive form promoted precocious oligodendrocyte specification in developing chick neural tube. Transcriptional co-repressors HDAC1 and HDAC2 compete with beta-catenin for TCF7L2 interaction to regulate downstream genes involved in oligodendrocyte differentiation. Thus, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.
Ye
Feng
F
Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, USA.
Chen
Ying
Y
Hoang
ThaoNguyen
T
Montgomery
Rusty L
RL
Zhao
Xian-hui
XH
Bu
Hong
H
Hu
Tom
T
Taketo
Makoto M
MM
van Es
Johan H
JH
Clevers
Hans
H
Hsieh
Jenny
J
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
Lu
Q Richard
QR
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001921:Brain / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D002642:Chick Embryo; D005260:Female; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology; D009154:Mutation; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000502:physiology; D051820:TCF Transcription Factors / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544895:Tcf7l2 protein, mouse; C553059:Tcf7l2 protein, rat; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; C533426:Hdac2 protein, rat; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases