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Regulation of the Follicle-Stimulating Hormone ß Gene by the LHX3 LIM-Homeodomain Transcription Factor

Department of Biology, Indiana University-Purdue University (B.E.W., G.E.P., J.J.S., P.K., K.S.T., L.R.B., S.C.C., S.J.R.); and Endocrine Discovery, Lilly Research Laboratories, Eli Lilly & Co. (K.W.S.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Dr. Simon J. Rhodes, Department of Biology, Indiana University-Purdue University, 723 West Michigan Street, Indianapolis, Indiana 46202-5132. E-mail: srhodes{at}iupui.edu.

FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH ß-subunit promoter, but not the proximal LHß promoter. The related LHX4 mammalian transcription factor can also induce FSHß promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein containing a Krüppel-associated box domain. Six LHX3-binding sites were characterized within the FSHß promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin. Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHß promoter and basal promoter activity in gonadotrope cells. Using quantitative methods, we show that the responses of the FSHß promoter to activin do not require induction of the LHX3 gene. By comparative genomics using the human FSHß promoter, we demonstrate structural and functional conservation of promoter induction by LHX3. We conclude that the LHX3 LIM homeodomain transcription factor is involved in activation of the FSH ß-subunit gene in the pituitary gonadotrope cell.

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