Splice variants of DOMINO control Drosophila circadian behavior and pacemaker neuron maintenance

Circadian clocks control daily rhythms in physiology. In Drosophila, the small ventral lateral neurons (sLNvs) expressing PIGMENT DISPERSING FACTOR (PDF) are the master pacemaker neurons. Despite the importance of sLNvs and PDF in circadian behavior, little is known about factors that control sLNvs maintenance and PDF accumulation. Here, we identify the Drosophila SWI2/SNF2 protein DOMINO (DOM) as a key regulator of circadian behavior. Depletion of DOM eliminates morning anticipation and impairs rhythmicity. Interestingly, the two splice variants of DOM, DOM-A and DOM-B have distinct circadian functions. DOM-A depletion leads to arrhythmic behavior, while DOM-B knockdown lengthens circadian period. Both DOM-A and DOM-B bind to the promotor regions of key pacemaker genes period and timeless, and regulate their protein expression. Furthermore, we identify that DOM-A is required for the maintenance of sLNvs and transcription of pdf. Lastly, constitutive activation of PDF-receptor signaling rescued the arrhythmia and period lengthening of DOM downregulation. Taken together, our findings reveal that splice variants of DOM play distinct roles in circadian rhythms through regulating abundance of pacemaker proteins and sLNvs maintenance.