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

Abstract

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.

Diurnal and Circadian Oscillations in Expression of Kisspeptin, Kisspeptin Receptor and Gonadotrophin‐Releasing Hormone 2 Genes in the Grass Puffer, A Semilunar‐Synchronised Spawner

“…We also observed that gnrh2 had one peak at CT9 within a day under DD conditions, suggesting that gnrh2 expression is under control of circadian mechanism. Circadian regulation of GnRH neural activity and gene expression has been reported in rodents and medaka . The different cyclic expression patterns of the three GnRH genes, kiss2 and kiss2r in the present study suggest that Kiss2 does not appear to directly regulate three GnRH genes.…”

NKX2-1 New Mutation Associated With Myoclonus, Dystonia, and Pituitary Involvement

“…TTF1 knockout mice lack the pituitary gland (Takuma et al, 1998 ). Postnatally it regulates GH and prolactin transcription in the rat pituitary (Lee et al, 2007 ) and has also been shown to play a role in the regulation of circadian changes in gonadotropin-releasing hormone (GnRH) expression (Matagne et al, 2012 ). Therefore, NKX2-1 haploinsufficiency is a plausible explanation for the symptoms of our patients.…”

A Role for the Transcription Factor Nk2 Homeobox 1 in Schizophrenia: Convergent Evidence from Animal and Human Studies

“…Some of these candidates were identified during the pre-GWAS period, with others based on GWAS studies. NKX2-1 is known to interact with a number of these genes (Thome et al, 1996 ; Perrone et al, 1999 ; Stober et al, 1999 ; Marin et al, 2000 ; Naltner et al, 2000 ; Ojeda et al, 2000 ; Stoykova et al, 2000 ; Kim et al, 2002 ; Leonard et al, 2002 ; Yi et al, 2002 ; Chojnacki and Weiss, 2004 ; Cui et al, 2005 ; Ide et al, 2005 ; Reynolds and Hoidal, 2005 ; Aghajani et al, 2006 ; Sanjuan et al, 2006 ; Takahashi et al, 2006 ; Benzel et al, 2007 ; Hashimoto et al, 2007 ; Son et al, 2007 ; Takao et al, 2007 ; Kahler et al, 2008 ; Zhou et al, 2008 ; Leon et al, 2009 ; Carney et al, 2010 ; Waddington et al, 2010 ; Goulburn et al, 2011 ; Zhang et al, 2011 ; Crisafulli et al, 2012 ; Matagne et al, 2012 ; Quednow et al, 2012 ; Li T. et al, 2013 ; Trotman et al, 2013 ; Zscheppang et al, 2013 ; Luo et al, 2014 ) (Table 1 ).…”

“…Neuroendocrine hypothalamic subnuclei involved in mating, fertility, reproduction, and the integration of reproduction with other homeostatic and environmental signals include the central part of the medial preoptic nucleus, the ventrolateral part of the ventromedial hypothalamic nucleus, the anteroventral periventricular nucleus, and the ventral premammillary nucleus (Lee et al, 2001 ; Magno et al, 2009 ; Matagne et al, 2012 ). In rodents, Nkx2-1 is highly expressed in the neuroendocrine hypothalamus.…”

“…In rodents, Nkx2-1 is highly expressed in the neuroendocrine hypothalamus. Nkx2-1 contributes to the control of sexual maturation in mice, with expression increasing abruptly at puberty in order to repress the transcription of genes that inhibit puberty (e.g., proenkephalin; Lee et al, 2001 ) and to activate genes that drive puberty (such as gonadotropin-releasing hormone) (Matagne et al, 2012 ). Nkx2-1 also participates in the maintenance of the female reproductive cycle, which necessitates changes in gonadotropin-releasing hormone (Ojeda et al, 2000 , 2006 ; Mastronardi et al, 2006 ; Provenzano et al, 2010 ).…”