TY - JOUR
T1 - CBP Histone Acetyltransferase Activity Regulates Embryonic Neural Differentiation in the Normal and Rubinstein-Taybi Syndrome Brain
AU - Wang, Jing
AU - Weaver, Ian C.G.
AU - Gauthier-Fisher, Andrée
AU - Wang, Haoran
AU - He, Ling
AU - Yeomans, John
AU - Wondisford, Frederic
AU - Kaplan, David R.
AU - Miller, Freda D.
N1 - Funding Information:
This work was supported by Canadian Institutes of Health Research (CIHR) grant MOP13958 to F.D.M. and D.R.K. F.D.M. and D.R.K. are Canada Research Chairs, and F.D.M. is a Howard Hughes Medical Institute International Research Scholar. J.W. and I.C.G.W. were supported by fellowships from the Hospital for Sick Children Foundation/Multiple Sclerosis Society of Canada, and the CIHR, respectively. We thank Bill Trimble, Dennis Aquino, and Kaplan/Miller laboratory members for advice and assistance.
PY - 2010/1/19
Y1 - 2010/1/19
N2 - Increasing evidence indicates that epigenetic changes regulate cell genesis. Here, we ask about neural precursors, focusing on CREB binding protein (CBP), a histone acetyltransferase that, when haploinsufficient, causes Rubinstein-Taybi syndrome (RTS), a genetic disorder with cognitive dysfunction. We show that neonatal cbp+/- mice are behaviorally impaired, displaying perturbed vocalization behavior. cbp haploinsufficiency or genetic knockdown with siRNAs inhibited differentiation of embryonic cortical precursors into all three neural lineages, coincident with decreased CBP binding and histone acetylation at promoters of neuronal and glial genes. Inhibition of histone deacetylation rescued these deficits. Moreover, CBP phosphorylation by atypical protein kinase C ζ was necessary for histone acetylation at neural gene promoters and appropriate differentiation. These data support a model in which environmental cues regulate CBP activity and histone acetylation to control neural precursor competency to differentiate, and indicate that cbp haploinsufficiency disrupts this mechanism, thereby likely causing cognitive dysfunction in RTS.
AB - Increasing evidence indicates that epigenetic changes regulate cell genesis. Here, we ask about neural precursors, focusing on CREB binding protein (CBP), a histone acetyltransferase that, when haploinsufficient, causes Rubinstein-Taybi syndrome (RTS), a genetic disorder with cognitive dysfunction. We show that neonatal cbp+/- mice are behaviorally impaired, displaying perturbed vocalization behavior. cbp haploinsufficiency or genetic knockdown with siRNAs inhibited differentiation of embryonic cortical precursors into all three neural lineages, coincident with decreased CBP binding and histone acetylation at promoters of neuronal and glial genes. Inhibition of histone deacetylation rescued these deficits. Moreover, CBP phosphorylation by atypical protein kinase C ζ was necessary for histone acetylation at neural gene promoters and appropriate differentiation. These data support a model in which environmental cues regulate CBP activity and histone acetylation to control neural precursor competency to differentiate, and indicate that cbp haploinsufficiency disrupts this mechanism, thereby likely causing cognitive dysfunction in RTS.
KW - DEVBIO
KW - MOLNEURO
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U2 - 10.1016/j.devcel.2009.10.023
DO - 10.1016/j.devcel.2009.10.023
M3 - Article
C2 - 20152182
AN - SCOPUS:74049144071
SN - 1534-5807
VL - 18
SP - 114
EP - 125
JO - Developmental Cell
JF - Developmental Cell
IS - 1
ER -