Abnormal skeletal patterning in embryos lacking a single Cbp allele: A partial similarity with Rubinstein–Taybi syndrome

Abstract

CBP is a transcriptional coactivator required by many transcription factors for transactivation. Rubinstein-Taybi syndrome, which is an autosomal dominant syndrome characterized by abnormal pattern formation, has been shown to be associated with mutations in the Cbp gene. Furthermore, Drosophila CBP is required in hedgehog signaling for the expression of decapentapleigic, the Drosophila homologue of bone morphogenetic protein. However, no direct evidence exists to indicate that loss of one copy of the mammalian Cbp gene affects pattern formation. Here, we show that various abnormalities occur at high frequency in the skeletal system of heterozygous Cbp-deficient mice resulting from a C57BL͞6-CBA ؋ BALB͞c cross. In support of a conserved signaling pathway for pattern formation in insects and mammals, the expression of Bmp7 was found to be reduced in the heterozygous mutants. The frequency of the different abnormalities was significantly lower in a C57BL͞6-CBA background, suggesting that the genetic background is an important determinant of the variability and severity of the anomalies seen in Rubinstein-Taybi syndrome patients.A protein that binds to the protein kinase A-phosphorylated form of cyclic AMP response element-binding protein (CREB) was originally identified and named CBP (1). CBP also binds to several components of the basal transcriptional machinery, including transcription factor IIB (2), RNA polymerase II holoenzyme complex (3), and the GCN5-like histone acetyltransferase, P͞CAF (4), suggesting that CBP serves as a CREB coactivator. In addition, CBP binds to multiple kinases, such as S6 kinase pp90 RSK (5) and cyclin-dependent kinases (6), and mediates the regulation of transcription by these kinases. The recent finding that CBP itself has histone acetyltransferase activity (7,8) suggests that it contributes to transcriptional activation by disrupting the repressive chromatin structure. CBP interacts with not only CREB but also with many other transcription factors,

Hippocampal Focal Knockout of CBP Affects Specific Histone Modifications, Long-Term Potentiation, and Long-Term Memory

“…However, it is possible that there are developmental confounds because of the use of CaMKIIa, which begins driving expression in all forebrain neurons after birth and reaches maximum expression over the next few weeks of life (Kojima et al, 1997). This could have consequences on the developing hippocampus considering a homozygous knockout of CBP is embryonic lethal (Tanaka et al, 1997). In this study, AAV-Cre was used to generate a complete CBP knockout in adult mice only in the dorsal hippocampus, thus reducing the possibility of confounding developmental or behavioral performance effects.…”

“…However, none of these Cbp genetically modified mice were designed to target a single brain region and only one generated a complete knockout of CBP, as a homozygous knockout of Cbp results in embryonic lethality (Tanaka et al, 1997). These mice, therefore, may have phenotypes reflecting residual CBP or compensatory mechanisms.…”

Subregion-specific p300 conditional knock-out mice exhibit long-term memory impairments

“…It is a possibility that CBP and p300 can function interchangeably during the formation of spatial memory, or that only the CBP function is required. Indeed, evidence for distinct functions for CBP and p300 has been shown (Tanaka et al 1997;Yao et al 1998;Kasper et al 2002Kasper et al , 2006Oliveira et al 2006). However, these hypotheses remain to be tested.…”

D1/D5 receptors and histone deacetylation mediate the Gateway Effect of LTP in hippocampal dentate gyrus

“…The generation of CBP+/2 mice was described previously (Tanaka et al 1997;Alarcon et al 2004). The WT mice used as control group were litter mates of the CBP+/2 mice.…”