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Clocks For All Seasons: Unravelling the Genetic Circadian and Interval Timing Mechanisms in the Mammalian Hypothalamus and Pituitary

Research output: Chapter in Book/Report/Conference proceedingConference contribution

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Original languageEnglish
Title of host publicationThe 2014 Meeting of the Society for Research on Biological Rhythms
Publication statusPublished - 14 Jun 2014

Abstract

There is powerful evidence that photoperiodism in seasonal organisms is driven by the circadian clockwork. The external co-incidence hypothesis of Erwin Bunning proposed that the circadian clock sets a photosensitive phase, which when exposed to light at a critical phase generates a long-photoperiod (LP) response. The molecular circuitry underpinning this model has been extensively explored in plants, but only recently have genetic mechanisms involved in mammals become clear. Thyroid hormones are crucial for driving seasonal reproduction, mediated by photoperiodic control of the de-iodinase enzyme (Dio2) in the ventral hypothalamus. Dio2 is elevated on LPs, leading to conversion of T4 to T3, and a seasonally-dependent T3-driven re-modelling of neuroendocrine circuits. Remarkably, the Dio2 gene is cAMP activated via hypothalamic TSH-receptors, which in turn are controlled by TSH hormone from the adjacent pituitary pars tuberalis (PT), the prime site of melatonin (MEL) action. In the PT, the TSHb gene is LP-activated. The up-stream molecular switch driving TSHb is Eya3, a member of the retinal determining gene family. Rhythmic MEL signals are proposed to drive a circadian oscillation in the PT of Eya3 via E-box mediated mechanism, leading to elevation of Eya3 12h after MEL onset. This only occurs in the absence of continued MEL-signalling, and is de-repressed on LPs (i.e. external co-incidence). Using a sheep-specific antibody, we have shown increased expression of EYA3 on LPs that is co-localised with TSHb in PT TSH-expressing cells. We propose a binary switching model is driving the response in the PT to LP; gradually switching individual cells from an inactive to active state. Finally, using EM, we describe major photoperiodic re-modelling of cells in the PT, driven by MEL signalling. The design principles of the mammalian photoperiodic clock are remarkably similar to those proposed for plants, where an analogous gene, Constans, fulfils an identical role to Eya3, and where epigenetic-regulated re-modelling drives photoperiodic responses.

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