Multiple and Overlapping Combinatorial Codes Orchestrate Hormonal Responsiveness and Dictate Cell-Specific Expression of the Genes Encoding Luteinizing Hormone

Indiana University Bloomington, Bloomington, Indiana, United States
Endocrine Reviews (Impact Factor: 21.06). 09/2004; 25(4):521-42. DOI: 10.1210/er.2003-0029
Source: PubMed


Normal reproductive function in mammals requires precise control of LH synthesis and secretion by gonadotropes of the anterior pituitary. Synthesis of LH requires expression of two genes [alpha-glycoprotein subunit (alphaGSU) and LHbeta] located on different chromosomes. Hormones from the hypothalamus and gonads modulate transcription of both genes as well as secretion of the biologically active LH heterodimer. In males and females, the transcriptional tone of the genes encoding alphaGSU and LHbeta reflects dynamic integration of a positive signal provided by GnRH from hypothalamic neurons and negative signals emanating from gonadal steroids. Although alphaGSU and LHbeta genes respond transcriptionally in the same manner to changes in hormonal input, different combinations of regulatory elements orchestrate their response. These hormone-responsive regulatory elements are also integral members of much larger combinatorial codes responsible for targeting expression of alphaGSU and LHbeta genes to gonadotropes. In this review, we will profile the genomic landscape of the promoter-regulatory region of both genes, depicting elements and factors that contribute to gonadotrope-specific expression and hormonal regulation. Within this context, we will highlight the different combinatorial codes that control transcriptional responses, particularly those that mediate the opposing effects of GnRH and one of the sex steroids, androgens. We will use this framework to suggest that GnRH and androgens attain the same transcriptional endpoint through combinatorial codes unique to alphaGSU and LHbeta. This parallelism permits the dynamic and coordinate regulation of two genes that encode a single hormone.

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    • "To develop this organ, various transcription factors are essential for organogenesis and maintenance of pituitary hormone production. Several approaches to clarify the molecular mechanisms have been used, and many transcription factors governing the basal and cell-specific expression have been discovered [1]. Transcription factors definitely recognize particular nucleotide sequences located near the target gene. "
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    ABSTRACT: Homeobox transcription factors are known to play crucial roles in the anterior lobe of the pituitary gland. During molecular cloning with the Yeast One-Hybrid System using a 5'-upstream region of the porcine Fshβ as a bait sequence, we have cloned a cDNA encoding a partial sequence of the retina-derived POU domain factor 1 (RPF1) from the porcine pituitary cDNA library and confirmed its specific binding to the bait sequence. In situ hybridization was performed to examine localization of Rpf1 and showed that this gene is expressed in the stem/progenitor cells of the rat pituitary primordium as well as the diencephalon and retina. In addition, real-time PCR demonstrated that Rpf1 transcripts are abundant in early embryonic periods but that this is followed by a decrease during pituitary development, indicating that this factor plays a role in differentiating cells of the pituitary. The transcriptional activity of RPF1 for genes of Prop1, Prrx1 and Prrx2, which were characterized as genes participating in the pituitary stem/progenitor cells by our group, was then examined with full-length cDNA obtained from the rat pituitary. RPF1 showed regulatory activity for PROP1 and PRRX2, but not for PRRX1. These results indicate the involvement of this retina-derived factor in pituitary development.
    Journal of Reproduction and Development 05/2014; 60(4). DOI:10.1262/jrd.2014-023 · 1.52 Impact Factor
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    • "LH and FSH are dimeric glycoproteins composed of a common α subunit (αGSU or CGA) and unique β subunits (LHB and FSHB), which confer biological specificity. Lhb and Fshb expression, which is rate-limiting in the production of the mature hormones, is under the control of several endocrine, paracrine, and autocrine factors [1], [2]. Most important for Lhb production is gonadotropin-releasing hormone (GnRH). "
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    ABSTRACT: Successful mammalian reproduction depends on proper synthesis of the pituitary-derived glycoprotein hormones, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Several transcription factors cooperate to activate cell-specific and hormone-regulated expression of the gonadotropin beta subunits (Lhb and Fshb). Among these, NR5A1 (steroidogenic factor 1; SF1) has been shown to directly bind to the Lhb promoter, mediate basal and gonadotropin-releasing hormone (GnRH)-stimulated Lhb transcription, and possibly directly regulate Fshb expression. Recently, the closely-related NR5A2 was shown to activate the rat Lhb promoter in vitro. Here, we further characterized the role of NR5A2 in regulating gonadotropin synthesis. Ectopically expressed NR5A2 directly activated the murine Lhb promoter in a manner identical to that of NR5A1, whereas neither factor activated the murine Fshb promoter. In LβT2 gonadotrope-like cells, depletion of endogenous NR5A1 or NR5A2 impaired basal and GnRH-stimulated Lhb and Fshb transcription. To analyze the physiological role of NR5A2 in gonadotropes in vivo, we generated mice with a gonadotrope-specific deletion of Nr5a2. In contrast with our in vitro data, these mice had normal pituitary Lhb and Fshb expression and intact fertility. Together, our data establish that NR5A2 can act in a non-redundant manner to regulate Lhb and Fshb transcription in vitro, but is dispensable in vivo.
    PLoS ONE 03/2013; 8(3):e59058. DOI:10.1371/journal.pone.0059058 · 3.23 Impact Factor
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    • "Lhb gene, whose regulatory mechanism has been elucidated and seems to be relatively conserved among the mammalian species (reviewed by [3]), regulations of Fshb gene are still under active investigation and it turns out to be species-specific due to genetic variations in the proximal promoter among several mammalian species [4]. Previous studies on GnRH-induced regulation of Fshb gene have successfully identified factors involved in the regulation of basal transcriptional machinery, which include cis-elements and transcription factors (reviewed by [4] [5]). "
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    ABSTRACT: Gonadotropin-releasing hormone (GnRH) regulates the synthesis and secretion of follicle-stimulating hormone (FSH) by stimulating the transcription of Fshβ gene. Our iTRAQ quantitative proteomics result showed that the abundance of α-actinin4 (ACTN4) increased in the nuclei of LβT2 cells upon GnRH induction. Using RNA interference, reverse transcription and real-time PCR, luciferase and transient transfection assays, we proved that ACTN4 is involved in the regulation of mouse Fshβ gene (mFshβ) transcription and its C-terminal calmodulin (CaM)-like domain is crucial for this process. Our study suggests that ACTN4 nuclear translocation mediates GnRH stimulation of mFshβ gene transcription.
    FEBS letters 05/2012; 586(10):1466-71. DOI:10.1016/j.febslet.2012.03.067 · 3.17 Impact Factor
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