TARGETING OF THE CREB GENE LEADS TO UP-REGULATION OF A NOVEL CREB MESSENGER-RNA ISOFORM

To define the role of cAMP signaling in gene control, we have generate d mice with a mutation in the cAMP response element binding protein (C REB) gene. Mice carrying this mutation are viable but show an impairme nt in memory consolidation, In the further analysis of these mice, we have found an up-regulation of a CREB isoform that bas not been descri bed previously, The new isoform, termed CREB beta, 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 tran scriptional rate, Due to the relatively low levels of expression in al l 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, t ogether with the specific deficiencies recently observed in these mice , suggest that it has a very specific role in compensating for CREB al pha and Delta in some, but not all, areas where CREB function has been implicated, Together with the up-regulation of the cAMP response elem ent modulator protein (CREM) mRNA and protein levels demonstrated prev iously in CREB mutant mice, we suggest that the up-regulation of CREB beta may also contribute to compensation within the CREB/ATF family of transcription factors, when CREB Delta and CREB alpha are absent.