Delivery of a cyclic adenosine 3 ',5 '-monophosphate response element-binding protein (CREB) mutant to seminiferous tubules results in impaired spermatogenesis

FSH binding to Sertoli cells is required for optimal production of sperm in mammals. The cAMP response element-binding protein (CREB) is a major media tor of FSH-induced changes in gene expression. To determine whether CREB is required for spermatogenesis, an adenovirus encoding a phosphorylation-def ective CREB mutant (AdCREBm1) was used to inhibit CREB activity in Sertoli cells. Addition of AdCREBm1 to primary rat Sertoli cell cultures completely abolished induction of the CREB-regulated c-fos gene. injection of an aden ovirus encoding beta -galactosidase into the rat testis seminiferous tubule s in, vivo demonstrated that predominately Sertoli cells were infected by a denovirus. AdCREBm1-directed expression of CREBm1 in seminiferous tubules d id not affect Sertoli cell viability, but resulted in the apoptosis of meio tic spermatocyte germ cells within 4 days of adenovirus injection into semi niferous tubules. Disrupted spermatogenesis, defined by at least a 75% redu ction of round spermatids, was observed in 42 +/- 5.8% of seminiferous tubu les 14 days after AdCREBm1 infection, whereas using this criteria, testes i njected with a control adenovirus did not display disrupted spermatogenesis . These data demonstrate that AdCREBm1 causes apoptosis and elimination of germ cells and suggest that CREB is required to produce a Sertoli cell-deri ved factor that is critical for germ cell survival.