Alternative Exon Splicing Controls a Translational Switch from Activator to Repressor Isoforms of Transcription Factor CREB during Spermatogenesis*

The cAMP/protein kinase A signaling pathway activates the cAMP-responsive transcription factor CREB. Here we describe a unique alternative RNA splicing event that occurs during the development of germ cells in the testis, resulting in a translational switch from an mRNA encoding activator CREB to an mRNA encoding novel inhibitor CREB isoforms (I-CREBs). Alternative splicing of an additional exon into the CREB mRNA in mid to late pachytene spermatocytes results in the premature termination of translation and consequent downstream reinitiation of translation producing I-CREBs. The I-CREBs down-regulate cAMP-activated gene expression by inhibiting activator CREB from binding to cAMP response elements. Further, the developmental stage-specific expression of I-CREBs in germ cells of the seminiferous tubules correlates with the cyclical down-regulation of activator CREB, suggesting that I-CREBs repress expression of the cAMP-inducible CREB gene as well as other genes transiently induced by cAMP during the 12-day cycle of spermatogenesis.