Follicle-stimulating hormone (FSH) transiently blocks FSH receptor transcription by increasing inhibitor of deoxyribonucleic acid binding/differentiation-2 and decreasing upstream stimulatory factor expression in rat Sertoli cells.
FSH acts through the FSH receptor (FSHR) to modulate cell processes that are required to support developing spermatozoa. Within the testis, only Sertoli cells possess receptors for FSH and are the major targets for this regulator of spermatogenesis. FSH stimulation of Sertoli cells for 24-48 h is known to induce Fshr mRNA expression through an E-box motif (CACGTG) located 25 bp upstream of the transcription start site. In contrast, FSH stimulation for 8 h inhibits Fshr transcription. DNA-protein binding studies performed using nuclear extracts from Sertoli cells show that protein binding to the Fshr promoter E-box was reduced 68% after 6 h of FSH stimulation but increased 191% over basal levels after 48 h of stimulation. The proteins binding to the Fshr E-box were identified as upstream stimulatory factor (USF)-1 and -2. FSH stimulation transiently decreased USF1 levels and increased the expression of the inhibitor of DNA binding/differentiation (ID)-2 repressor protein with the same kinetics as the decreased USF/E-box interactions. Overexpression of ID2 resulted in a dose-dependent decrease in USF-driven Fshr promoter activity in the MSC-1 Sertoli cell line, and ID2 inhibited USF binding to the Fshr E-box. Together, these studies suggest that stimulation of Sertoli cells with FSH transiently decreases expression of the USF1 activator and induces accumulation of the ID2 repressor, to block USF binding to the Fshr promoter and delay activation of Fshr transcription. This FSH-regulated mechanism may explain the cyclical changes in Fshr expression that occurs in Sertoli cells in vivo.
Viswanathan
Pushpa
P
Department of Cell Biology and Physiology, Magee Women's Research Institute, University of Pittsburgh, Center for Research in Reproductive Physiology, Pittsburgh, Pennsylvania 15213, USA.
Wood
Michelle A
MA
Walker
William H
WH
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006728:Hormones / Q000494:pharmacology*; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D011962:Receptors, FSH / Q000235:genetics*; D012708:Sertoli Cells / Q000378:metabolism; D051720:Upstream Stimulatory Factors / Q000378:metabolism* / Q000502:physiology
D006728:Hormones; D051797:Inhibitor of Differentiation Protein 2; D011962:Receptors, FSH; D051720:Upstream Stimulatory Factors; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP