CREM, a master-switch of the transcriptional cascade in male germ cells

In eukaryotes, transcriptional regulation upon stimulation of the adenylyl cyclase signalling pathway is mediated by a family of cAMP-responsive nuclear factors. The CREB and CREM transcription factors are activated by phosphorylation of a key serine residue by kinase stimulated by cyclic AMP, calcium, growth factors and stress signals. Phosphorylation allows recruitment of CBP (CREB Binding Protein), a large co-activator that contacts the general transcriptional machinery. The CREM gene plays a key physiological and developmental role within the hypothalamic-pituitary-gonadal axis. CREM is highly expressed in postmeiotic cells upon a striking developmental switch regulated by the pituitary hormone FSH. CREM-mutant mice generated by homologous recombination reveal that spermatogenesis stops at the first step of spermiogenesis. Late spermatids are completely absent while there is a significant increase in apoptotic germ cells. Mutant male mice completely lack spermatozoa, a phenotype reminiscent of cases of human infertility. Interestingly, in male germ cells, CREM is not phosphorylated but associates with ACT, a member of the LIM-only class of proteins that has intrinsic transcriptional activity. Thus, in some circumstance, CREM can bypass the classical requirement for phosphorylation and association with CBP.