|[Frontiers in Bioscience 1, d266-269, September 1, 1996]|
CREM: A TRANSCRIPTIONAL MASTER SWITCH DURING THE SPERMATOGENESIS
François Nantel and Paolo Sassone-Corsi
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, BP 163, ILLKIRCH Cedex, C.U. de Strasbourg, France
Received 08/17/96; Accepted 08/21/96; On-line 09/01/96
The CREM gene presents many remarkable characteristics. By alternative splicing, CREM isoforms may contain one of two distinct, alternative, DNA binding domains which confer distinct affinities for CREs (7, 8). In contrast to CREB which encode exclusively activators of gene transcription, the CREM gene may encode both activators (tau) and repressors (alpha, ß, gamma) (8, 9). Moreover, CREM has a tissue- and cell-specific pattern of expression since it is found at high levels in the testis and neuroendocrine tissues (7, 10). Finally, CREM is an early response gene, a property conferred by an intronic promoter that is strongly inducible by cAMP (11). This internal promoter (P2) is located upstream from the DNA binding domains and drives the expression of ICER (Inducible cAMP early repressor), a powerful repressor of the cAMP-induced transcription that is the smallest transcription factor know to this day. The expression of the P2 promoter occurs through activation of four CRE sequences which are organized in tandem within the promoter. Following the induction of the ICER protein, this inhibit its own transcription by binding the four CRE sequences (11). Thus, there is a CREM negative autoregulatory loop, which ensures various cycles of transcriptional inducibility (11).
The CREM gene is highly expressed in the adult testis (10). Levels of CREM transcripts are low in prepubertal testis and only the repressor isoforms (alpha, ß) are detected. However, during puberty, transcripts encoding the activator form CREMtau accumulate to high levels in pachytene spermatocytes and spermatids (10). Interestingly, the CREMtau protein is not detected in spermatocytes but only in haploid spermatids (12). Many haploid genes have been identified as potential CREM target genes since they contain CREs in their promoters. The genes encoding RT7, transition protein 1 and calspermin have all been shown to be activated by CREMtau (12-14).
The switch in CREM expression pattern during spermatogenesis is under the control of the gonadotropin FSH (15). Surgical removal of the pituitary gland from adult rats leads to loss of CREMtau expression in the testis and hypophysectomization of prepubertal rats prevents the developmental switch in CREM expression (15). The physiological role of pituitary hormones on CREM expression was also studied in the hamster, a seasonal breeder characterized by testicular atrophy and spermatogenic arrest during winter. Hamsters kept under conditions of short photoperiod (SP) show a reduction in serum concentrations of FSH, LH and prolactin, accompanied by testicular atrophy and absence of CREM expression. Hormonal levels and CREM expression are restored when the animals are placed under long photoperiod (LP). Injection of FSH, but not LH or prolactin, in hamsters kept under SP increases CREMtau expression to levels found in sexually active animals (15). This observation clearly indicated that FSH is the hormone regulating CREMtau expression. The molecular mechanism by which FSH activates CREMtau expression in germ cell is under investigation. The FSH receptor is located on somatic Sertoli cell and not on the germ cells. During their developmental process, the germ cells are kept in intimate contact with the somatic Sertoli cells. It has been suggested that a paracrine factor, possibly a peptide, is released by the Sertoli cells following FSH stimulation and that this factor is responsible for the switch in CREM expression. Nuclear run-on experiments show that the increased CREMtau expression in germ cell is not associated with an increase in the rate of transcription initiation of the gene. Instead, the increase in CREMtau is characterized by the use of an alternative polyadenylation site, located in close proximity to the stop codon, that excludes 9 of the 10 AUUUA mRNA destabilization elements found on the 3' untranslated region of the CREM gene (15).
Recently, it has been shown that CREM may be implicated in the regulation of Sertoli cell function. In cultured primary Sertoli cells, FSH induces an increase in cAMP levels which results in the activation of the P2 promoter of CREM and then in an increase in the expression of ICER (16). Interestingly, the kinetics of ICER expression correlate with the transcriptional down-regulation of the FHS receptor. Given that ICER is a potent transcriptional repressor and that the FSH receptor gene has a CRE element in its promoter, it was postulated that ICER could be implicated in the reduction in FSH receptor gene expression. DNA-binding and expression studies have demonstrated that ICER is involved in the long-term desensitization of the FSH-receptor in Sertoli cells (16).