Pituitary hormone FSH directs the CREM functional switch during spermatogenesis

The CREM (cyclic AMP-responsive element modulator) gene encodes multiple regulators of the cAMP-transcriptional response by alternative splicing. A developmental switch in CREM expression occurs during spermatogenesis, whereby CREM function is converted from an antagonist to an activator (CREM tau; ref. 2) which accumulates to extremely high levels from the premeiotic spermatocyte stage onwards. To define the physiological mechanisms controlling the CREM developmental switch, we have hypophysectomized rats and observed the extinction of CREM tau expression in testis, thereby demonstrating a central role of the pituitary-hypothalamic axis. We then used the seasonal-dependent modulation of spermatogenesis in hamsters to dissect the hormonal programme controlling this developmental process. By this approach, combined with direct administration of pituitary-derived hormones, we have established that follicle-stimulating hormone (FSH) is responsible for the CREM switch. FSH appears to regulate CREM expression by alternative polyadenylation, which results in a dramatic enhancement of transcript stability.