Seasonal synchronization based on day length (photoperiod) allows organisms to anticipate environmental change. Photoperiodic decoding relies on circadian clocks, but the underlying molecular pathways have remained elusive [1]. In mammals and birds, photoperiodic responses depend crucially on expression of thyrotrophin β subunit RNA (TSHβ) in the pars tuberalis (PT) of the pituitary gland [2-4]. Now, using our well-characterized Soay sheep model [2], we describe a molecular switch governing TSHβ transcription through the circadian clock. Central to this is a conserved D element in the TSHβ promoter, controlled by the circadian transcription factor thyrotroph embryonic factor (Tef). In the PT, long-day exposure rapidly induces expression of the coactivator eyes absent 3 (Eya3), which synergizes with Tef to maximize TSHβ transcription. The pineal hormone melatonin, secreted nocturnally, sets the phase of rhythmic Eya3 expression in the PT to peak 12 hr after nightfall. Additionally, nocturnal melatonin levels directly suppress Eya3 expression. Together, these effects form a switch triggering a strong morning peak of Eya3 expression under long days. Species variability in the TSHβ D element influences sensitivity to TEF, reflecting species variability in photoperiodic responsiveness. Our findings define a molecular pathway linking the circadian clock to the evolution of seasonal timing in mammals.
Photoperiodic responses enable animals to adapt their physiology to predictable patterns of seasonal environmental change. In mammals, this depends on pineal melatonin secretion and effects in the hypothalamus, but the cellular and molecular substrates of its action are poorly understood. The recent identification of a mammalian orthologue of the avian gonadotrophin-inhibitory hormone gene has led to interest in its possible involvement in seasonal breeding. In long-day breeding Syrian hamsters, hypothalamic RFamide-related peptide (RFRP) expression is increased by exposure to long photoperiod. Because, opposite to hamsters, sheep are short-day breeders, we predicted that a conserved role in mammalian reproductive activation would decrease RFRP expression in sheep under a long photoperiod. We cloned the ovine RFRP cDNA and examined its expression pattern in Soay sheep acclimated to a 16 : 8 h or 8 : 16 h light /dark cycle (LP and SP, respectively). RFRP was expressed widely in the sheep hypothalamus and increased modestly overall with exposure to LP. Interestingly, RFRP expression in the ependymal cells surrounding the base of the third ventricle was highly photoperiodic, with levels being undetectable in animals held on SP but consistently high under LP. These data are inconsistent with a conserved reproductive role for RFRP across mammals. Additionally, we cloned the ovine homologue of the cognate RFRP receptor, rfr-2 (NPFF1) and found localised expression in the suprachiasmatic nuclei and in the pars tuberalis. Taken together, these data strengthen the emerging view that interplay between ependymal cells and the pars tuberalis might be important for the seasonal timing system.
At temperate latitudes, many mammals and birds show internally timed, long-term changes in seasonal physiology, synchronised to the seasons by changing day length (photoperiod). Photoperiodic control of thyroid hormone levels in the hypothalamus dictates the timing. This is effected through reciprocal regulation of thyroid hormone deiodinase gene expression. The local synthesis of type 2 deiodinase (Dio2) promotes triiodothyronine (T3) production and summer biology, whereas type 3 deiodinase (Dio3) promotes T3 degradation and winter biology. In the present study, we investigated the extent to which the hypothalamic expression of Dio2 and Dio3 is circannually regulated in the Soay sheep, a short-day breeding mammal. Male sheep were exposed to a long photoperiod (LP; 16 : 24 h light/dark cycle) or a short photoperiod (SP; 8 : 24 h light/dark cycle), for up to 28 weeks to establish four different endocrine states: (i) LP animals in a spring/summer-like state of reproductive arrest; (ii) LP refractory (LPR) animals showing spontaneous reproductive reactivation; (iii) SP animals showing autumn/winter-like reproductive activation; and (iv) SP refractory (SPR) animals showing spontaneous reproductive arrest. A complex pattern of hypothalamic Dio2 and Dio3 expression was observed, revealing distinctive photoperiod-driven and internally timed effects for both genes. The patterns of expression differed both spatially and temporally, with phases of peak Dio2 expression in the median eminence and tuberoinfundibular sulcus, as well as in the paraventricular zone (PVZ) (maximal under LP), whereas Dio3 expression was always confined to the PVZ (maximal under SP). These effects likely reflect the distinct roles of these enzymes in the localised control of hypothalamic T3 levels. The spontaneous decline in Dio2 and spontaneous increase in Dio3 in LPR animals occurred with a corresponding decline in thyroid-stimulating hormone β expression in the neighbouring pars tuberalis (PT), although this relationship did not hold for the corresponding Dio2 increase/Dio3 decrease seen in SPR animals. We conclude that internally timed and spatially regulated changes in Dio2 and Dio3 expression may drive the cycling between breeding and nonbreeding states in long-lived seasonal species, and may be either PT-dependent or PT-independent at different phases of the circannual cycle.
The annual cycle of changing day length (photoperiod) is widely used by animals to synchronise their biology to environmental seasonality. In mammals, melatonin is the key hormonal relay for the photoperiodic message, governing thyroid-stimulating hormone (TSH) production in the pars tuberalis (PT) of the pituitary stalk. TSH acts on neighbouring hypothalamic cells known as tanycytes, which in turn control hypothalamic function through effects on thyroid hormone (TH) signalling, mediated by changes in expression of the type II and III deiodinases (Dio2 and Dio3, respectively). Among seasonally breeding rodents, voles of the genus Microtus are notable for a high degree of sensitivity to nutritional and social cues, which act in concert with photoperiod to control reproductive status. In the present study, we investigated whether the TSH/Dio2/Dio3 signalling pathway of female common voles (Microtus arvalis) shows a similar degree of photoperiodic sensitivity to that described in other seasonal mammal species. Additionally, we sought to determine whether the plant metabolite 6-methoxy-2-benzoxazolinone (6-MBOA), described previously as promoting reproductive activation in voles, had any influence on the TSH/Dio2/Dio3 system. Our data demonstrate a high degree of photoperiodic sensitivity in this species, with no observable effects of 6-MBOA on upstream pituitary/hypothalamic gene expression. Further studies are required to characterise how photoperiodic and nutritional signals interact to modulate hypothalamic TH signalling pathways in mammals.
Thyroid hormone (TH) is an ancestral signal linked to seasonal life history transitions throughout vertebrates. TH action depends upon tissue-localized regulation of levels of active TH (triiodothyronine, T3), through spatiotemporal expression of thyroid hormone deiodinase (dio) genes. We investigated the dio gene family in juvenile Atlantic salmon (Salmo salar) parr, which prepare for seaward migration in the spring (smoltification) through TH-dependent changes in physiology. We identified two type 2 deiodinase paralogs, dio2a and dio2b, responsible for conversion of thyroxine (T4) to T3. During smoltification, dio2b was induced in the brain and gills in zones of cell proliferation following increasing day length. Contrastingly, dio2a expression was induced in the gills by transfer to salt water (SW), with the magnitude of the response proportional to the plasma chloride level. This response reflected a selective enrichment for osmotic response elements (OREs) in the dio2a promoter region. Transcriptomic profiling of gill tissue from fish transferred to SW plus or minus the deiodinase inhibitor, iopanoic acid, revealed SW-induced increases in cellular respiration as the principal consequence of gill dio2 activity. Divergent evolution of dio2 paralogs supports organ-specific timing of the TH-dependent events governing the phenotypic plasticity required for migration to sea.
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