Novel cyclic adenosine 3',5'-monophosphate (cAMP) response element modulator theta isoforms expressed by two newly identified cAMP-responsive promoters active in the testis.

cAMP signaling contributes to the control of the developmental progression of germ cells during the spermatogenic cycle. Genes regulated by cAMP include those encoding transcription factors such as the cAMP-responsive element modulator (CREM). The disruption of CREM gene expression in crem null mice results in arrest of spermatogenesis and infertility. The transcriptional control of the CREM gene is attributed to two promoters, P1 and P2. The P1 promoter constitutively activates the synthesis of messenger RNAs encoding activator (tau) and repressor (alpha) forms of CREM, whereas the cAMP-responsive P2 promoter activates the formation of messenger RNAs encoding the inducible cAMP early repressor. Here we report the identification of two additional promoters in the CREM gene, P3 and P4, that in the rat testis encode two novel transcriptional activator CREM isoforms, termed CREM theta1 and CREM theta2, respectively. Notably, the P3 and P4 promoters are activated by cAMP-dependent protein kinase, thereby providing cAMP-regulated transcription of CREM activators in addition to the established cAMP-regulated inducible cAMP early repressor. Analysis ex vivo of CREM gene expression in temporally staged segments of the seminiferous tubule during the spermatogenic cycle shows that the activities of the P1, P3, and P4 promoters are independently regulated. Our identification of the cAMP-activated P3 and P4 promoters that direct expression of the novel theta1 and theta2 activator isoforms of CREM brings further insight into the complex expression of the CREM gene during germ cell development and may have implications in understanding the control of fertility.