The impact of thyroid hormone in seasonal breeding has a restricted transcriptional signature

Abstract

Thyroid hormone (TH) directs seasonal breeding through reciprocal regulation of TH deiodinase (Dio2/Dio3) gene expression in tanycytes in the ependymal zone of the medio-basal hypothalamus (MBH). Thyrotropin secretion by the pars tuberalis (PT) is a major photoperiod-dependent upstream regulator of Dio2/Dio3 gene expression. Long days enhance thyrotropin production, which increases Dio2 expression and suppresses Dio3 expression, thereby heightening TH signaling in the MBH. Short days appear to exert the converse effect. Here, we combined endocrine profiling and transcriptomics to understand how photoperiod and TH control the ovine reproductive status through effects on hypothalamic function. Almost 3000 genes showed altered hypothalamic expression between the breeding- and non-breeding seasons, showing gene ontology enrichment for cell signaling, epigenetics and neural plasticity. In contrast, acute switching from a short (SP) to a long photoperiod (LP) affected the expression of a much smaller core of 134 LP-responsive genes, including a canonical group previously linked to photoperiodic synchronization. Reproductive switch-off at the end of the winter breeding season was completely blocked by thyroidectomy (THX), despite a very modest effect on the hypothalamic transcriptome. Only 49 genes displayed altered expression between intact and THX ewes, including less than 10% of the LP-induced gene set. Neuroanatomical mapping showed that many LP-induced genes were expressed in the PT, independently of the TH status. In contrast, TH-sensitive seasonal genes were principally expressed in the ependymal zone. These data highlight the distinctions between seasonal remodeling effects, which appear to be largely independent of TH, and TH-dependent localised effects which are permissive for transition to the non-breeding state.

A unifying hypothesis for control of body weight and reproduction in seasonally breeding mammals

“…55 It has also been postulated to play a role in the regulation of energy balance because it is highly expressed in white adipose tissue, which is in direct proportion to the level of adiposity. 56 This apparent difference between sheep and rodents needs to be confirmed by other techniques, although, if substantiated, this may be an interesting point of distinction between long day and short day breeders. 55 Evidence for a neuroendocrine role for chemerin has come from F344 rats Despite the clear evidence for a role of retinoic acid in photoperiod signalling in the hypothalamus of both the F344 rat and Siberian hamster, there are no data available to indicate a role for any retinoic acid signalling genes in sheep.…”

“…68 DNA methylation is increased under long photoperiods in the Siberian hamster and this appears to be linked to reproductive competency. 56 Hence, it remains to be investigated whether these PT-expressed genes control regulation directly in tanycytes. 56 Hence, it remains to be investigated whether these PT-expressed genes control regulation directly in tanycytes.…”

An integrative view of mammalian seasonal neuroendocrinology

“…The D1 receptor on the other hand stimulates cAMP production via activation of adenylate cyclase in neurones . In the ovine PT, only the D1 receptor is expressed . Furthermore in an acute melatonin infusion paradigm, D1 receptor is one of the most highly differentially expressed genes in the PT .…”

“…Whether this model is present in other circannual species is unknown, although it illustrates that mechanisms pertinent to cell and tissue plasticity might be involved in timekeeping devices. Indeed, a large number of genes involved in cellular plasticity and differentiation are differentially expressed according to the season in PT and MBH . It has been proposed that seasonal timing relies on histogenic processes .…”

“…Cellular differentiation and development are regulated by epigenetic processes. Interestingly, a number of enzymes involved in chromatin remodelling are expressed in the ovine PT, where their expression is increased under LP . The histone methyltransferase EZH2, a member of the PRC2 complex that lays down the repressive H3K27me3 mark, is one of these.…”