TTF1, a homeodomain containing transcription factor, contributes to regulating periodic oscillations in GnRH gene expression

• Published in: Journal of neuroendocrinology Vol. 24; no. 6; pp. 916 - 929
• Main Authors: Matagne, Valerie, Kim, Jae Geun, Ryu, Byung Jun, Hur, Min Kyu, Kim, Min Sung, Kim, Kyungjin, Park, Byong Seo, Damante, Giuseppe, Smiley, Gregory, Lee, Byung Ju, Ojeda, Sergio R.
• Format: Journal Article
• Language: English
• Published: 01.06.2012
• ISSN: 0953-8194; 1365-2826
• DOI: 10.1111/j.1365-2826.2012.02302.x

Thyroid transcription factor 1 (TTF1), a member of the NK 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 gonadotropin-releasing hormone (GnRH). Here we show that Ttf1 mRNA abundance vary in a diurnal and melatonin-dependent fashion in the preoptic area (POA) 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 siRNA-mediated Ttf1 gene silencing. TTF1 trans-activates GnRH transcription by binding to two sites in the GnRH promoter. Rat GnRH neurons 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 . In 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.