DOMINO的剪接变体控制果蝇的昼夜节律行为和起搏器神经元维持。,PLOS Genetics

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DOMINO的剪接变体控制果蝇的昼夜节律行为和起搏器神经元维持。
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-10-28 , DOI: 10.1371/journal.pgen.1008474
Zhenxing Liu ₁ , Christine A Tabuloc ₂ , Yongbo Xue ₁ , Yao Cai ₂ , Pearson Mcintire ₁ , Ye Niu ₁ , Vu H Lam ₂ , Joanna C Chiu ₂ , Yong Zhang ₁

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昼夜节律控制行为和生理的日常节律。在果蝇中，表达颜料分散因子（PDF）的小腹外侧神经元（sLNvs）是产生起搏节律的主要起搏器神经元。尽管sLNvs和PDF在昼夜节律行为中很重要，但对于控制sLNvs维持和PDF积累的因素知之甚少。在这里，我们确定果蝇SWI2 / SNF2蛋白DOMINO（DOM）是昼夜节律行为的关键调节因子。昼夜神经元中DOM的耗竭消除了光暗周期下早晨的预期活动，并在恒定的黑暗中损害了行为节律。有趣的是，DOM的两个主要剪接变体DOM-A和DOM-B具有不同的昼夜节律功能。DOM-A耗竭主要导致心律失常行为，而DOM-B敲低延长了昼夜节律周期，而不会影响昼夜节律。DOM-A和DOM-B都与周期性起搏器关键基因的启动子区域周期性结合，并调节其蛋白质表达。但是，我们确定只有DOM-A才能维持sLNvs和pdf转录。最后，PDF受体信号传导的本构激活挽救了心律不齐和DOM下调的周期延长。综上所述，我们的发现揭示了DOM的两个剪接变体通过调节起搏器蛋白的丰度和sLNvs的维持在昼夜节律中发挥着不同的作用。我们确定仅DOM-A即可维持sLNvs和pdf转录。最后，PDF受体信号传导的本构激活挽救了心律不齐和DOM下调的周期延长。综上所述，我们的发现揭示了DOM的两个剪接变体通过调节起搏器蛋白的丰度和sLNvs的维持在昼夜节律中发挥着不同的作用。我们确定仅DOM-A即可维持sLNvs和pdf转录。最后，PDF受体信号传导的本构激活挽救了心律不齐和DOM下调的周期延长。综上所述，我们的发现揭示了DOM的两个剪接变体通过调节起搏器蛋白的丰度和sLNvs的维持在昼夜节律中扮演着不同的角色。

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

Circadian clocks control daily rhythms in behavior and physiology. In Drosophila, the small ventral lateral neurons (sLNvs) expressing PIGMENT DISPERSING FACTOR (PDF) are the master pacemaker neurons generating locomotor rhythms. 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 in circadian neurons eliminates morning anticipatory activity under light dark cycle and impairs behavioral rhythmicity in constant darkness. Interestingly, the two major splice variants of DOM, DOM-A and DOM-B have distinct circadian functions. DOM-A depletion mainly leads to arrhythmic behavior, while DOM-B knockdown lengthens circadian period without affecting the circadian rhythmicity. Both DOM-A and DOM-B bind to the promoter regions of key pacemaker genes period and timeless, and regulate their protein expression. However, we identify that only 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 two splice variants of DOM play distinct roles in circadian rhythms through regulating abundance of pacemaker proteins and sLNvs maintenance.

更新日期：2019-11-01

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