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Endocrinology Vol. 142, No. 2 948-954
Copyright © 2001 by The Endocrine Society

ARTICLES

Delivery of a Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein (CREB) Mutant to Seminiferous Tubules Results in Impaired Spermatogenesis1

M. Joe Scobey, Suzanne Bertera, Jeremy P. Somers, Simon C. Watkins, Anthony J. Zeleznik and William H. Walker

Department of Cell Biology and Physiology, University of Pittsburgh (M.J.S., J.P.S., S.C.W., A.J.Z., W.H.W.), and Division of Immunogenetics, Children’s Hospital of Pittsburgh, (S.B.), Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Dr. William H. Walker, 820 Scaife Hall, Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261. E-mail: walkerw+{at}pitt.edu

FSH binding to Sertoli cells is required for optimal production of sperm in mammals. The cAMP response element-binding protein (CREB) is a major mediator of FSH-induced changes in gene expression. To determine whether CREB is required for spermatogenesis, an adenovirus encoding a phosphorylation-defective 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 adenovirus encoding ß-galactosidase into the rat testis seminiferous tubules in vivo demonstrated that predominately Sertoli cells were infected by adenovirus. AdCREBm1-directed expression of CREBm1 in seminiferous tubules did not affect Sertoli cell viability, but resulted in the apoptosis of meiotic spermatocyte germ cells within 4 days of adenovirus injection into seminiferous tubules. Disrupted spermatogenesis, defined by at least a 75% reduction of round spermatids, was observed in 42 ± 5.8% of seminiferous tubules 14 days after AdCREBm1 infection, whereas using this criteria, testes injected 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-derived factor that is critical for germ cell survival.




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