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Activin Regulates Luteinizing Hormone ß-Subunit Gene Expression through Smad-Binding and Homeobox Elements

Departments of Reproductive Medicine and Neuroscience (D.C., V.G.T., P.L.M.), Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674; and Genetics of Development and Disease Branch (C.-X.D.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

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

LH ß-subunit (LHß), which is essential for ovulation and reproductive fitness, is synthesized specifically in pituitary gonadotropes. In this study, we show that LHß gene expression is induced by activin in mouse primary pituitary cells if the cells are treated within 24 h after dispersion in culture. Furthermore, male mice deficient in Smad3, and therefore in activin signaling, have lower expression of both LHß and FSHß mRNAs compared with their wild-type littermates. Using the LßT2 immortalized mouse gonadotrope cell line that endogenously expresses LH, we identify specific elements in the regulatory region of the rat LHß gene necessary for its induction by activin. Activin responsiveness is conferred by a promoter-proximal region located –121/–86 from the transcriptional start site. Maximal LHß induction by activin requires a homeobox element (HB) and a 5'-early growth response (Egr) site found in this region of the promoter. Juxtaposed to the HB are three Smad-binding elements (SBEs), which are essential for LHß induction. Interestingly, two of the SBEs are also critical for basal expression of the LHß gene. We demonstrate that Smad proteins are necessary and sufficient for activin induction of the LHß gene. Furthermore, Smad proteins can bind one of the identified SBEs. In addition to binding this SBE, Smad proteins interact with pituitary homeobox 1 (Ptx-1) and orthodenticle homeobox 1 (Otx-1), which can bind the HB located close to the Smad-binding site. Thus, activin induction of LHß gene expression requires a combination of several transcription factors, both basal and activin induced, as well as cooperation between multiple DNA elements.

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