The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1

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.