Circadian clock mechanism driving mammalian photoperiodism

Abstract

RESULTS 89Epigenetic regulation of the seasonal transcriptome within the Pars 90 tuberalis 91Seasonally breeding sheep are a well-established photoperiodic model for the 92 study of neuroendocrine mechanisms underpinning seasonal physiology 14,28,29 . 93Using a study design that compared the effects of transfer from long 94 photoperiod (LP) to short photoperiod (SP) with transfer from SP to LP (Fig. 1b), 95we collected pars tuberalis (PT) tissue at 1,7 and 28 days after transfer, with 96 collections timed for 4-h after lights on (ZT4), when EYA3 expression peaks 97 under LP 22,24,29 . Changes in prolactin concentrations 29-31 confirmed 98 photoperiodic hormone responses, as well as LP activation of EYA3, and 99 inverse expression patterns of TSHβ (LP marker) and CHGA (SP marker) ( Fig. 100 1b, Supplementary Fig. 1a-d, n=4), validating this paradigm. 101Comparing LP day 28 to SP day 28 by electron microscopy we found an 102 increased nuclear diameter, equating to an approximate doubling in volume of 103 PT thyrotrophs, and a marked reduction in chromatin density on LP (Fig. 1c,

Gerald Lincoln: A man for all seasons

“…The demonstration that thyrotrophs in the ovine pars tuberalis exist in one of two states, either βTSH positive in the long day state under the control of Eya 3, or βTSH negative in the short day state characterised by high chromogranin A expression, strongly supports the cyclical histogenesis theory 51 . Moreover, Gerald was enthusiastic about recent work demonstrating an epigenetic component to the mechanism by which a changing daily melatonin signal might be detected by the pars tuberalis but then interact with a rhythmically changing cellular chromatin state, perhaps an annual recapitulation of developmental mechanisms regulating βTSH cells 42 …”

“…In sheep maintained in constant light to suppress endogenous melatonin production, infusion of melatonin was found to acutely induce cry1 expression and suppress other clock genes, indicating a causal link, 39 and in vitro analyses also identified the immediate early gene egr1 as a potential mediator of the effects of melatonin 40 . Subsequent transcriptomic analysis of sheep pars tuberalis identified a large number of genes that had altered phasing in long vs short photoperiods, 41 and bmal2, eya3 and TAC1 have all emerged as pathway candidates in transducing the melatonin signal into a seasonal drive from the pars tuberalis 42‐44 . However, somewhat unexpectedly, sheep maintained for a prolonged time on long days showed clock gene phasing in the pars tuberalis that corresponded to the ambient melatonin phasing, yet downstream seasonal physiology reversed from the initial photoperiodic state 45 .…”

“…40 Subsequent transcriptomic analysis of sheep pars tuberalis identified a large number of genes that had altered phasing in long vs short photoperiods, 41 and bmal2, eya3 and TAC1 have all emerged as pathway candidates in transducing the melatonin signal into a seasonal drive from the pars tuberalis. [42][43][44] However, somewhat unexpectedly, sheep maintained for a prolonged time on long days showed clock gene phasing in the pars tuberalis that corresponded to the ambient melatonin phasing, yet downstream seasonal physiology reversed from the initial photoperiodic state. 45 Gerald considered this as important evidence for the existence of intrinsic circannual mechanisms that were independent of melatonin-regulated timers.…”

“…51 Moreover, Gerald was enthusiastic about recent work demonstrating an epigenetic component to the mechanism by which a changing daily melatonin signal might be detected by the pars tuberalis but then interact with a rhythmically changing cellular chromatin state, perhaps an annual recapitulation of developmental mechanisms regulating βTSH cells. 42 Towards the end of his career, Gerald* became particularly interested in the question of when and how circannual rhythmicity might have evolved in primitive organisms despite their relatively short life span. 46 His broad understanding of biology stimulated this interest, and he eloquently presented a beautiful example of how annual rhythmicity occurs across the haploid and diploid components of the life cycle of the marine dinoflagellate Alexandrium (Figure 5).…”

International Neuroendocrine Federation: Year 2020 in Review

“…Several member societies have also focused on the thyrotropic and gonadotropic axes. Regarding the former, Wood et al 6 of the British Society for Neuroendocrinology elucidate an epigenetic circadian clock mechanism underlying photoperiodism in sheep, based on a coincidence timer regulated by a flip‐flop switch consisting of the transcriptional activator BMAL2 and its repressor DEC1. Together, under the influence of photoperiod‐specific pineal melatonin secretion, these increase or decrease thyrotropin expression in the pars tuberalis of the pituitary under the influence of the transcriptional co‐activator EYA3.…”