Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.

<h4>Background</h4>The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiat...

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Autores principales:	Moritz J Rossner, Henrik Oster, Sven P Wichert, Lisa Reinecke, Michael C Wehr, Johannes Reinecke, Gregor Eichele, Reshma Taneja, Klaus-Armin Nave
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/86559e37fc204688aaed8a707e16e04e
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spelling	oai:doaj.org-article:86559e37fc204688aaed8a707e16e04e2021-11-25T06:11:31ZDisturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.1932-620310.1371/journal.pone.0002762https://doaj.org/article/86559e37fc204688aaed8a707e16e04e2008-07-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18648504/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiatric-, metabolic disorders and even cancer. However, the molecular mechanisms leading to the disintegration of tissue-specific clocks are complex and not well understood.<h4>Methodology/principal findings</h4>Based on their circadian expression and cell culture experiments, the basic Helix-Loop-Helix (bHLH) transcription factors SHARP-1(Dec2) and SHARP-2(Stra13/Dec1) were proposed as novel negative regulators of the molecular clock. To address their function in vivo, we generated Sharp-1 and Sharp-2 single and double mutant mice. Our experiments reveal critical roles for both factors in regulating period length, tissue-specific control of clock gene expression and entrainment to external cues. Light-pulse experiments and rapid delays of the light-dark cycle (experimental jet lag) unravel complementary functions for SHARP-1 and SHARP-2 in controlling activity phase resetting kinetics. Moreover, we show that SHARP-1 and 2 can serve dual functions as repressors and co-activators of mammalian clock gene expression in a context-specific manner. This correlates with increased amplitudes of Per2 expression in the cortex and liver and a decrease in the suprachiasmatic nucleus (SCN) of double mutant mice.<h4>Conclusions/significance</h4>The existence of separate mechanisms regulating phase of entrainment, rhythm amplitude and period length has been postulated before. The differential effects of Sharp-deficiency on rhythmicity and behavioral re-entrainment, coupled to tissue-dependent regulatory functions, provide a new mechanistic basis to further understand the complex process of clock synchronizations.Moritz J RossnerHenrik OsterSven P WichertLisa ReineckeMichael C WehrJohannes ReineckeGregor EicheleReshma TanejaKlaus-Armin NavePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 7, p e2762 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Moritz J Rossner Henrik Oster Sven P Wichert Lisa Reinecke Michael C Wehr Johannes Reinecke Gregor Eichele Reshma Taneja Klaus-Armin Nave Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
description	<h4>Background</h4>The circadian system provides the basis to anticipate and cope with daily recurrent challenges to maintain the organisms' homeostasis. De-synchronization of circadian feedback oscillators in humans causes 'jet lag', likely contributes to sleep-, psychiatric-, metabolic disorders and even cancer. However, the molecular mechanisms leading to the disintegration of tissue-specific clocks are complex and not well understood.<h4>Methodology/principal findings</h4>Based on their circadian expression and cell culture experiments, the basic Helix-Loop-Helix (bHLH) transcription factors SHARP-1(Dec2) and SHARP-2(Stra13/Dec1) were proposed as novel negative regulators of the molecular clock. To address their function in vivo, we generated Sharp-1 and Sharp-2 single and double mutant mice. Our experiments reveal critical roles for both factors in regulating period length, tissue-specific control of clock gene expression and entrainment to external cues. Light-pulse experiments and rapid delays of the light-dark cycle (experimental jet lag) unravel complementary functions for SHARP-1 and SHARP-2 in controlling activity phase resetting kinetics. Moreover, we show that SHARP-1 and 2 can serve dual functions as repressors and co-activators of mammalian clock gene expression in a context-specific manner. This correlates with increased amplitudes of Per2 expression in the cortex and liver and a decrease in the suprachiasmatic nucleus (SCN) of double mutant mice.<h4>Conclusions/significance</h4>The existence of separate mechanisms regulating phase of entrainment, rhythm amplitude and period length has been postulated before. The differential effects of Sharp-deficiency on rhythmicity and behavioral re-entrainment, coupled to tissue-dependent regulatory functions, provide a new mechanistic basis to further understand the complex process of clock synchronizations.
format	article
author	Moritz J Rossner Henrik Oster Sven P Wichert Lisa Reinecke Michael C Wehr Johannes Reinecke Gregor Eichele Reshma Taneja Klaus-Armin Nave
author_facet	Moritz J Rossner Henrik Oster Sven P Wichert Lisa Reinecke Michael C Wehr Johannes Reinecke Gregor Eichele Reshma Taneja Klaus-Armin Nave
author_sort	Moritz J Rossner
title	Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
title_short	Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
title_full	Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
title_fullStr	Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
title_full_unstemmed	Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.
title_sort	disturbed clockwork resetting in sharp-1 and sharp-2 single and double mutant mice.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/86559e37fc204688aaed8a707e16e04e
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Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice.

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