Abstract
SummaryCircadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour. Here, we describe a mouse mutant where the central mammalian pacemaker, the suprachiasmatic nucleus (SCN), has been genetically ablated by conditional deletion of the transcription factor Zfhx3 in the developing hypothalamus. Mutants were arrhythmic over the light-dark cycle and in constant darkness. Moreover, rhythms of metabolic parameters were ablated in vivo although molecular oscillations in the liver maintained some rhythmicity. Despite disruptions to SCN cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity although activity levels in mutants were altered. This work highlights a critical role for Zfhx3 in the development of a functional SCN, while its genetic ablation further defines the contribution of SCN circuitry in orchestrating physiological and behavioral responses to environmental signals.
Highlights
Circadian rhythms are endogenous 24-hour oscillations present in almost all organisms (Dunlap, 1999)
Circadian rhythms persist in almost all organisms and are crucial for maintaining appropriate timing in physiology and behaviour
Despite disruptions to suprachiasmatic nucleus (SCN) cell identity and circuitry, mutants could still anticipate food availability, yet other zeitgebers - including social cues from cage-mates - were ineffective in restoring rhythmicity activity levels in mutants were altered
Summary
Circadian rhythms are endogenous 24-hour oscillations present in almost all organisms (Dunlap, 1999). Cellular clocks at tissue and organ levels are maintained and synchronized by a central circadian oscillator in the hypothalamus: the suprachiasmatic nucleus (SCN). Peripheral tissue oscillators, relay cues back to the SCN and, in doing so, form robust circadian clocks both at the level of individual tissues/organs and the organism (Weaver, 1998). The strongest entraining factor (or Zeitgeber) is light, whereas other factors, such as food availability and social cues, can play significant roles (Refinetti, 2015). Maintaining and resetting this synchronous activity is critical for health and well-being. Desynchrony has been shown to have adverse physiological consequences both in animal models and humans (Jagannath et al, 2017; Roenneberg and Merrow, 2016) and is a known hallmark of many psychiatric disorders (Banks et al, 2016; Ben-Hamo et al, 2016; Landgraf et al, 2016)
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