Abstract
The PAS (PER-ARNT-SIM) helix-loop-helix transcription factor BMAL1 (also known as MOP3) is an essential component of the circadian pacemaker in mammals. Here we show that the retinoic acid receptor-related orphan receptor RORalpha (NR1F1) directly activates transcription of Bmal1 through two conserved RORalpha response elements that are required for cell-autonomous transcriptional oscillation of Bmal1 mRNA. Positive involvement of RORalpha in generation of the Bmal1 circadian oscillation was verified by behavioral analyses of RORalpha-deficient staggerer mice that showed aberrant locomotor activity and unstable rhythmicity. In cultured cells, loss of endogenous RORalpha protein resulted in a dampened circadian rhythm of Bmal1 transcription, further indicating that RORalpha is a functional component of the cell-autonomous core circadian clock. These results indicate that RORalpha acts to promote Bmal1 transcription, thereby maintaining a robust circadian rhythm.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ARNTL Transcription Factors
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Behavior, Animal / physiology
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Cell Line
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Circadian Rhythm / genetics*
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Circadian Rhythm / physiology*
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DNA / genetics
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DNA / metabolism
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Gene Expression Regulation*
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Mice
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Mutation / genetics
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / deficiency
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Response Elements / genetics
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / genetics*
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Transcription, Genetic / genetics*
Substances
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ARNTL Transcription Factors
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Bmal1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Nuclear Receptor Subfamily 1, Group F, Member 1
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Rora protein, mouse
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Trans-Activators
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Transcription Factors
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DNA