Abstract
Disrupted-in-schizophrenia 1 (DISC1) is a scaffold protein that has been implicated in multiple mental disorders. DISC1 is known to regulate neuronal proliferation, signaling, and intracellular calcium homeostasis, as well as neurodevelopment. Although DISC1 was linked to sleep-associated behaviors, whether DISC1 functions in the circadian rhythm has not been determined yet. In this work, we revealed that Disc1 expression exhibits daily oscillating pattern and is regulated by binding of circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1) heterodimer to E-box sequences in its promoter. Interestingly, Disc1 deficiency increases the ubiquitination of BMAL1 and de-stabilizes it, thereby reducing its protein levels. DISC1 inhibits the activity of GSK3β, which promotes BMAL1 ubiquitination, suggesting that DISC1 regulates BMAL1 stability by inhibiting its ubiquitination. Moreover, Disc1-deficient cells and mice show reduced expression of other circadian genes. Finally, Disc1-LI (Disc1 knockout) mice exhibit damped circadian physiology and behaviors. Collectively, these findings demonstrate that the oscillation of DISC1 expression is under the control of CLOCK and BMAL1, and that DISC1 contributes to the core circadian system by regulating BMAL1 stability.
Highlights
Anticipating the time of day is crucial for organisms that live under recurrent sunlight
In this study, we showed that Disrupted-in-schizophrenia 1 (DISC1) has novel functions on the molecular circadian clock, further expanding the repertoire of the diverse roles of DISC1 in various cell types
The functional interaction between DISC1 and the molecular clock is reciprocal; DISC1 modulates the quality of the molecular clock by regulating the Glycogen synthase kinase 3β (GSK3β)-mediated Brain and muscle Arnt-like protein-1 (BMAL1) stability and, at the same time, DISC1 expression itself is under control of Circadian locomotor output cycles kaput (CLOCK)/ BMAL1, displaying an oscillating expression pattern according to circadian time (Supplementary Fig. 5)
Summary
Anticipating the time of day is crucial for organisms that live under recurrent sunlight. Transcription–translation feedback loop (TTFL) of circadian genes ensures this cycle, which keeps the circadian clock ticking even without external time cues[5]. In the mammalian TTFL system, the main component is the heterodimer consisting of Circadian locomotor output cycles kaput (CLOCK) and Brain and muscle Arnt-like protein-1 (BMAL1), which binds to E-box sequences of target genes for transcriptional enhancement[6,7]. In this way, the CLOCK/BMAL1 heterodimer upregulates core clock genes, including Period (PERs), Cryptochrome (CRYs), and Nuclear receptor subfamily 1 (Nr1d1)[5]. The action of CLOCK/BMAL1 heterodimer is negatively regulated by PERs and CRYs, completing the TTFL8,9
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