Targeting of the CREB gene leads to up-regulation of a novel CREB mRNA isoform

Abstract

To define the role of cAMP signaling in gene control, we have generated mice with a mutation in the cAMP response element binding protein (CREB) gene. Mice carrying this mutation are viable but show an impairment in memory consolidation. In the further analysis of these mice, we have found an up-regulation of a CREB isoform that has not been described previously. The new isoform, termed CREBβ, has nearly the same transactivation potential as the other CREB isoforms and is expressed ubiquitiously. The up-regulation appears to be due to an increase in alternative splicing or mRNA stability, but not to an increase in transcriptional rate. Due to the relatively low levels of expression in all tissues, the role of this isoform is likely to be minor in the wild-type mouse. However, its dramatic up-regulation in the mutant mouse, together with the specific deficiencies recently observed in these mice, suggest that it has a very specific role in compensating for CREBα and Δ in some, but not all, areas where CREB function has been implicated. Together with the up-regulation of the cAMP response element modulator protein (CREM) mRNA and protein levels demonstrated previously in CREB mutant mice, we suggest that the up-regulation of CREBβ may also contribute to compensation within the CREB/ATF family of transcription factors, when CREBΔ and CREBα are absent.