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Pituitary Homeobox 2 Regulates Adrenal4 Binding Protein/Steroidogenic Factor-1 Gene Transcription in the Pituitary Gonadotrope through Interaction with the Intronic Enhancer

Division for Sex Differentiation (Y.S., M.Z., T.K., S.O., K.-i.M.), National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki 444-8787, Japan; Department of Bioengineering (C.Y., T.T.), Graduate School of Engineering, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan; Department of Experimental Medical Science (T.A.H.), Lund University, SE-22184 Lund, Sweden; and Laboratoire de génétique moléculaire (J.D.), Institut de Recherches Cliniques de Montréal, Montréal, Québec, Canada H2W 1R7

Address all correspondence and requests for reprints to: Professor Ken-ichirou Morohashi, Ph.D., Division for Sex Differentiation, National Institute for Basic Biology, National Institutes of Natural Sciences, Myodaiji-cho, Okazaki 444-8787, Japan. E-mail: moro{at}nibb.ac.jp.

Ad4BP/SF-1 [adrenal4 binding protein/steroidogenic factor-1 (NR5A1)] is a factor important for animal reproduction and endocrine regulation, and its expression is tightly regulated in the gonad, adrenal gland, ventromedial hypothalamic nucleus, and pituitary gonadotrope. Despite its functional significance in the pituitary, the mechanisms underlying pituitary-specific expression of the gene remain to be uncovered. In this study, we demonstrate by transgenic mouse assays that the pituitary gonadotrope-specific enhancer is localized within the sixth intron of the gene. Functionally, the enhancer recapitulates endogenous Ad4BP/SF-1 expression in the fetal Rathke’s pouch to the adult pituitary gonadotrope. Structurally, the enhancer consists of several elements conserved among animal species. Mutational analyses confirmed the significance of these elements for the enhancer function. One of these elements was able to interact both in vitro and in vivo with Pitx2 (pituitary homeobox 2), demonstrating that pituitary homeobox 2 regulates Ad4BP/SF-1 gene transcription in the pituitary gonadotrope via interaction with the gonadotrope-specific enhancer.