Role of transcription factors CREB and CREM in cAMP-regulated transcription during spermatogenesis.

The cAMP response element binding protein (CREB) and the cAMP-responsive element modulator (CREM) are cyclically expressed at high levels during spermatogenesis. Cyclical expression of CREB and CREM in germ and somatic Sertoli cells correlates with the fluctuations in cAMP signaling induced by the pituitary gonadotropic hormones FSH and LH both during sexual maturation of the testis and during the 12-day cycles of spermatogenesis that occur in the adult testis. CREB and CREM are expressed at different times during the spermatogenic cycle, undergo programmed sequential switches from activator to repressor isoforms by mechanisms of alternative exon splicing and promoter usage, and are autoregulated by cAMP signaling in opposing directions. cAMP response elements located in the promoter of the CREB gene upregulate the expression of activator CREBs, whereas cAMP autoregulatory response elements in the internal promoter of the CREM gene induce expression of repressor CREM isoforms. The complex mechanisms for the regulation of the expression of CREB and CREM in the testis appear to reflect critical adaptations for regulating key target genes essential for the development of germ cells.