Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein

Abstract

CREB-binding protein (CBP) is a transcriptional co-activator which is required by many transcription factors. Rubinstein-Taybi syndrome (RTS), which is an autosomal dominant syndrome characterized by abnormal pattern formation, is associated with mutations in the human CBP gene. Various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice, but some features of RTS such as cardiac anomalies do not, suggesting that some symptoms of RTS are caused by a dominant-negative mechanism. Here we report the characterization of homozygous Cbp-deficient mice. Homozygous mutants died around E10.5-E12.5, apparently as a result of massive hemorrhage caused by defective blood vessel formation in the central nervous system, and exhibited apparent developmental retardation as well as delays in both primitive and definitive hematopoiesis. Cbp-deficient embryos exhibited defective neural tube closure which was similar to those observed in twist-deficient embryos. However, a decrease in the level of twist expression was not observed in Cbp-deficient embryos. Anomalous heart formation, a feature of RTS patients and mice mutated in the CBP-related molecule, p300, was not observed in Cbp-deficient embryos. Since both Cbp and p300 are ubiquitously expressed in embryonic tissues including the developing heart, these results suggest that cardiac anomalies observed in RTS patients may be caused by a dominant negative effect of mutant CBP.

Distinct roles for CREB-binding protein and p300 in hematopoietic stem cell self-renewal

“…To further define the role of CBP and p300 in hematopoiesis, we studied the effect of the complete absence of either protein in HSC self-renewal and differentiation. Others have reported defective primitive hematopoiesis (i.e., yolk sac) in CBP nullizygous mice (18) or mice homozygous for a truncated form of CBP (19). However, the study of HSC during definitive hematopoiesis (i.e., in FL and, ultimately, in adult animals), which can be detected in the embryo beginning at Ϸembryonic day 11 (E11; ref.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Interestingly, an analysis of the distribution of the p300 messenger RNA (mRNA) during mouse development showed the elevated expression in the neural tissue, suggesting the involvement of this enzyme in neural development. Consistently, knocking out CBP or p300 leads to an open neural tube, potentially reflecting defects in twist (without changes in twist expression) or other transcription factors, such as paired box 3 (PAX3) and activating enhancer binding protein 2 (AP2), thereby affecting neural development [49,50]. Neural tube closure typically begins at E8.5 and spreads along neural folds; however, in CBP-null embryos, different types of neural tube closure defects are observed.…”

“…Neural tube closure typically begins at E8.5 and spreads along neural folds; however, in CBP-null embryos, different types of neural tube closure defects are observed. Hemorrhaging in the telencephalon and mesencephalon, reflecting defective vasculature, has also been observed and hypothesized as the primary cause of embryonic death [50].…”

A Small Molecule Activator of p300/CBP Histone Acetyltransferase Promotes Survival and Neurite Growth in a Cellular Model of Parkinson’s Disease

“…The global transcriptional co-activator p300/CBP is a potent HAT that plays essential roles in nervous system development (Lopez-Atalaya et al 2014;Sheikh 2014;Tanaka et al 2000;Yao et al 1998). p300/CBP HAT is recruited to DNA by direct interaction with specific transcription factors, which enhances transcriptional activity by acetylation of histones proximal to the promoter region.…”