CREM, short for cAMP-responsive element modulator, is a transcription factor that encodes both repressors and activators of cAMP-dependent transcription in a tissue-and developmentally-regulated manner [1]. It plays a key role in the hypothalamic-pituitary axis and is involved in the cAMP signaling pathway. In male germ cells, it functions as a master-switch regulating post-meiotic gene expression, and its regulation is also crucial in spermatogenesis [1,2]. Genetic models, especially mouse models, have been essential in studying CREM's functions.

In CREM-deficient male mice (generated by homologous recombination), spermatogenesis arrests at the first step of spermiogenesis, late spermatids are absent, and there is a ten-fold increase in germ cell apoptosis [4,6,7]. This phenotype is similar to some cases of human infertility, indicating CREM's vital role in male fertility [2,7]. In addition, in human spermatogenesis, a switch from CREM repressor to activator expression occurs in normospermic men, while in patients with round spermatid maturation arrest, only CREM repressors are expressed, suggesting that the absence of "the CREM switch" may be associated with spermatogenic arrest [2]. In CD4+ T cells, CREM regulates different effector cytokines, thus being an important determinant of central T helper cell functions [3]. In systemic lupus erythematosus, CREM expression in T cells is abnormal and may play a role in its pathogenesis [5].

In conclusion, CREM is a crucial transcription factor regulating male germ cell differentiation and apoptosis, with a significant impact on male fertility. Its abnormal regulation is associated with spermatogenic arrest and may be involved in diseases like systemic lupus erythematosus. Mouse models with CREM deficiency have been instrumental in uncovering these roles, providing insights into the underlying mechanisms of related diseases and potential therapeutic targets.