Thyroid Transcription Factor 1, a Homeodomain Containing Transcription Factor, Contributes to Regulating Periodic Oscillations in GnRH Gene Expression

V. Matagne, J. G. Kim, B. J. Ryu, M. K. Hur, M. S. Kim, K. Kim, B. S. Park, G. Damante, G. Smiley, B. J. Lee, S. R. Ojeda

    Research output: Contribution to journalArticle

    12 Scopus citations

    Abstract

    Thyroid transcription factor 1 (TTF1), a member of the Nkx family of transcription factors required for basal forebrain morphogenesis, functions in the postnatal hypothalamus as a transcriptional regulator of genes encoding neuromodulators and hypophysiotrophic peptides. One of these peptides is gonadotrophin-releasing hormone (GnRH). In the present study, we show that Ttf1 mRNA abundance varies in a diurnal and melatonin-dependent fashion in the preoptic area of the rat, with maximal Ttf1 expression attained during the dark phase of the light/dark cycle, preceding the nocturnal peak in GnRH mRNA content. GnRH promoter activity oscillates in a circadian manner in GT1-7 cells, and this pattern is enhanced by TTF1 and blunted by small interfering RNA-mediated Ttf1 gene silencing. TTF1 transactivates GnRH transcription by binding to two sites in the GnRH promoter. Rat GnRH neurones in situ contain key proteins components of the positive (BMAL1, CLOCK) and negative (PER1) limbs of the circadian oscillator, and these proteins repress Ttf1 promoter activity in vitro. By contrast, Ttf1 transcription is activated by CRY1, a clock component required for circadian rhythmicity. In turn, TTF1 represses transcription of Rev-erbα, a heme receptor that controls circadian transcription within the positive limb of the circadian oscillator. These findings suggest that TTF1 is a component of the molecular machinery controlling circadian oscillations in GnRH gene transcription.

    Original languageEnglish (US)
    Pages (from-to)916-929
    Number of pages14
    JournalJournal of Neuroendocrinology
    Volume24
    Issue number6
    DOIs
    StatePublished - Jun 1 2012

    Keywords

    • Circadian rhythm
    • Clock genes
    • GnRH gene expression
    • TTF1
    • Transcriptional control

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Endocrinology
    • Endocrine and Autonomic Systems
    • Cellular and Molecular Neuroscience

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