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Nuclear Factor Y and Steroidogenic Factor 1 Physically and Functionally Interact to Contribute to Cell-Specific Expression of the Mouse Follicle-Stimulating Hormone-ß Gene

Department of Reproductive Medicine, University of California, San Diego, La Jolla, California 92093-0674

Address all correspondence and requests for reprints to: Pamela L. Mellon, Ph.D., Department of Reproductive Medicine, 0674, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}ucsd.edu.

FSH is a heterodimeric glycoprotein hormone secreted from the gonadotrope cell population of the anterior pituitary. Despite its crucial role in mammalian reproduction, very little is known about regulation of the FSH ß-subunit gene at the molecular level. In this report, we examine the basis for cell-specific expression of FSHß using the mouse LßT2 and T3-1 gonadotrope-derived cell lines. Characterization of the hormonal content of LßT2 and T3-1 cells at the protein level classifies these cells as relatively mature and immature gonadotropes, respectively. We studied LßT2 cell-specific expression of FSHß using 398 bp of the mouse FSHß regulatory region linked to a luciferase reporter gene in transient transfection assays. This mouse FSHß promoter can direct reporter gene expression specifically to LßT2 cells when compared with other pituitary- and non-pituitary-derived cell lines, including T3-1 cells. Furthermore, it is induced by activin, and interruption of the autocrine activin loop in LßT2 cells by the addition of follistatin reduces its expression. Truncation analysis indicates that several regions of the promoter are involved in this specificity and that these can be dissociated from activin regulation. We identify binding sites for the orphan nuclear receptor steroidogenic factor-1 and the heterotrimeric transcription factor nuclear factor Y and show that these elements functionally interact to regulate FSHß gene expression in an LßT2 cell-specific manner. Moreover, steroidogenic factor-1 and nuclear factor Y are shown to physically interact with each other. This study is the first to demonstrate the presence of basal FSHß protein in LßT2 cells and to identify specific elements within the FSHß promoter that contribute to basal and cell-specific expression of the gene.

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