CBP Histone Acetyltransferase Activity Regulates Embryonic Neural Differentiation in the Normal and Rubinstein-Taybi Syndrome Brain

Jing Wang, Ian C.G. Weaver, Andrée Gauthier-Fisher, Haoran Wang, Ling He, John Yeomans, Frederic Wondisford, David R. Kaplan, Freda D. Miller

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)114-125
Number of pages12
JournalDevelopmental Cell
Volume18
Issue number1
DOIs
StatePublished - Jan 19 2010

Keywords

  • DEVBIO
  • MOLNEURO

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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