Thyroid Hormone Signalling Genes Are Regulated by Photoperiod in the Hypothalamus of F344 Rats

Abstract

Seasonal animals adapt their physiology and behaviour in anticipation of climate change to optimise survival of their offspring. Intra-hypothalamic thyroid hormone signalling plays an important role in seasonal responses in mammals and birds. In the F344 rat, photoperiod stimulates profound changes in food intake, body weight and reproductive status. Previous investigations of the F344 rat have suggested a role for thyroid hormone metabolism, but have only considered Dio2 expression, which was elevated in long day photoperiods. Microarray analysis was used to identify time-dependent changes in photoperiod responsive genes, which may underlie the photoperiod-dependent phenotypes of the juvenile F344 rat. The most significant changes are those related to thyroid hormone metabolism and transport. Using photoperiod manipulations and melatonin injections into long day photoperiod (LD) rats to mimic short day (SD), we show photoinduction and photosuppression gene expression profiles and melatonin responsiveness of genes by in situ hybridization; TSHβ, CGA, Dio2 and Oatp1c1 genes were all elevated in LD whilst in SD, Dio3 and MCT-8 mRNA were increased. NPY was elevated in SD whilst GALP increased in LD. The photoinduction and photosuppression profiles for GALP were compared to that of GHRH with GALP expression following GHRH temporally. We also reveal gene sets involved in photoperiodic responses, including retinoic acid and Wnt/ß-catenin signalling. This study extends our knowledge of hypothalamic regulation by photoperiod, by revealing large temporal changes in expression of thyroid hormone signalling genes following photoperiod switch. Surprisingly, large changes in hypothalamic thyroid hormone levels or TRH expression were not detected. Expression of NPY and GALP, two genes known to regulate GHRH, were also changed by photoperiod. Whether these genes could provide links between thyroid hormone signalling and the regulation of the growth axis remains to be investigated.

Dual signal transduction pathways activated by TSH receptors in rat primary tanycyte cultures

“…However, the applicability of the present findings may be more generic rather than merely applicable to mammals that are normally associated with seasons, as most laboratory strains of rats have the potential to respond to photoperiods with physiological changes following olfactory bulbectomy (Nelson & Zucker 1981) or after manipulation of testosteronenegative feedback (Wallen et al 1987). Moreover, the F344 rat strain does show physiological responses to photoperiods in terms of food intake and body weight (Ross et al 2011) and increases in Dio2 expression in the ependymal layer following i.c.v. administration of TSH (Helfer et al 2013).…”

“…To investigate the signal transduction mechanism of the TSH receptor in the hypothalamic ependymal layer, we chose to utilise primary cell cultures of these cells from 10-day-old rat brains, as described by Prevot et al (2003). First, as found in other species, Tsh receptor mRNA expression was confirmed by in situ hybridisation in the hypothalamus of 10-day-old rats, confined to the cells adjacent to the third ventricle (Hanon et al 2008, Nakao et al 2008, Ross et al 2011, Herwig et al 2013. Using primary ependymal layer cell cultures prepared from 10-day-old rats, we investigated the signal transduction mechanism used by TSH receptors to transduce hormone binding in these cells.…”

“…Expression of Dio2 is stimulated in tanycytes in a variety of situations, including starvation, which is caused by an unknown mechanism (Coppola et al 2007), inflammatory conditions, which are caused by an NFkB-dependent signalling mechanism (de Vries et al 2014, Wittmann et al 2014, and long-day photoperiods, which are caused by thyroid stimulating hormone (TSH) of pars tuberalis origin (Hanon et al 2008, Nakao et al 2008, Helfer et al 2013, Herwig et al 2013, Klosen et al 2013. TSH receptors are highly localised within the ventral region of the ependyma lining the third ventricle, a region that is composed mainly of tanycytes (Ross et al 2011, Herwig et al 2013. I.c.v.…”

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

“…Raldh1 protein is transported along the length of the tanycyte fibres (Shearer et al, 2010), which have been shown to contact Agrp/Npy neurons in the hypothalamus (Coppola et al, 2007), potentially releasing RA immediately adjacent to the target cells. This novel pathway provides a new route by which TH may promote expression of neuronal Agrp to increase appetite (Varela et al, 2012) and may also provide a mechanism by which TH could increase Ghrh to promote growth (Ross et al, 2011). The potential also exists for this to be a mechanism by which TH controls neurogenesis given the recent finding of RA's control of cell proliferation in the neurogenic regions of the hypothalamus (Shearer et al, 2012b).…”

Strong pituitary and hypothalamic responses to photoperiod but not to 6-methoxy-2-benzoxazolinone in female common voles (Microtus arvalis)

“…The Dio2 gene encodes the enzyme that converts thyroxine (T4) into biologically active triidothyronine (T3), whereas Dio3 is responsible for degrading T4 and T3 to inactive metabolites [28]. Depending on the species, the release of TSH from PT may trigger upregulation of Dio2 expression (Soay sheep and Syrian hamster Mesocricetus auratus), downregulation of Dio3 expression (Siberian hamster Phodopus sungorus) or reciprocal regulation of both deiodinases (European hamster Cricetus cricetus and Fischer F344 strain rats) [2,19,20,43,45]. The balance between Dio2 and Dio3 determines local concentrations of T3 in the mediobasal hypothalamus (MBH) and hence seasonal changes in the activity of the hypothalamo-pituitary-gonadal axis.…”