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

Autoři: Zhenxing Liu aff001;  Christine A. Tabuloc aff002;  Yongbo Xue aff001;  Yao Cai aff002;  Pearson Mcintire aff001;  Ye Niu aff001;  Vu H. Lam aff002;  Joanna C. Chiu aff002;  Yong Zhang aff001
Působiště autorů: Department of Biology, University of Nevada Reno, Reno, NV, United States of America aff001;  Department of Entomology and Nematology, University of California Davis, Davis, CA, United States of America aff002
Vyšlo v časopise: Splice variants of DOMINO control Drosophila circadian behavior and pacemaker neuron maintenance. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008474
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008474


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.

Klíčová slova:

Circadian oscillators – Circadian rhythms – Drosophila melanogaster – Gene expression – Chronobiology – Neurons – Pacemakers – RNA interference


1. Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE, Thomas TL, et al. Circadian rhythms from multiple oscillators: Lessons from diverse organisms. Nature Reviews Genetics. 2005;6(7):544–56. doi: 10.1038/nrg1633 WOS:000230245000012. 15951747

2. Hardin PE, Panda S. Circadian timekeeping and output mechanisms in animals. Curr Opin Neurobiol. 2013;23(5):724–31. doi: 10.1016/j.conb.2013.02.018 23731779; PubMed Central PMCID: PMC3973145.

3. Tataroglu O, Emery P. The molecular ticks of the Drosophila circadian clock. Current Opinion in Insect Science. 2015;7:51–7. doi: 10.1016/j.cois.2015.01.002 WOS:000369016700010. 26120561

4. Nitabach MN, Taghert PH. Organization of the Drosophila circadian control circuit. Curr Biol. 2008;18(2):R84–93. doi: 10.1016/j.cub.2007.11.061 18211849.

5. Grima B, Chelot E, Xia R, Rouyer F. Morning and evening peaks of activity rely on different clock neurons of the Drosophila brain. Nature. 2004;431(7010):869–73. doi: 10.1038/nature02935 15483616.

6. Stoleru D, Peng Y, Agosto J, Rosbash M. Coupled oscillators control morning and evening locomotor behaviour of Drosophila. Nature. 2004;431(7010):862–8. doi: 10.1038/nature02926 15483615.

7. Gorostiza EA, Depetris-Chauvin A, Frenkel L, Pirez N, Ceriani MF. Circadian pacemaker neurons change synaptic contacts across the day. Curr Biol. 2014;24(18):2161–7. doi: 10.1016/j.cub.2014.07.063 25155512; PubMed Central PMCID: PMC4175170.

8. Sivachenko A, Li Y, Abruzzi KC, Rosbash M. The transcription factor Mef2 links the Drosophila core clock to Fas2, neuronal morphology, and circadian behavior. Neuron. 2013;79(2):281–92. doi: 10.1016/j.neuron.2013.05.015 23889933; PubMed Central PMCID: PMC3859024.

9. Depetris-Chauvin A, Fernandez-Gamba A, Gorostiza EA, Herrero A, Castano EM, Ceriani MF. Mmp1 Processing of the PDF Neuropeptide Regulates Circadian Structural Plasticity of Pacemaker Neurons. Plos Genetics. 2014;10(10). ARTN e100470010.1371/journal.pgen.1004700. WOS:000344650700063.

10. HelfrichForster C. Development of pigment-dispersing hormone-immunoreactive neurons in the nervous system of Drosophila melanogaster. Journal of Comparative Neurology. 1997;380(3):335–54. doi: 10.1002/(sici)1096-9861(19970414)380:3<335::aid-cne4>3.0.co;2-3 WOS:A1997WQ86000004. 9087517

11. Renn SCP, Park JH, Rosbash M, Hall JC, Taghert PH. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell. 1999;99(7):791–802. doi: 10.1016/s0092-8674(00)81676-1 WOS:000084488200012. 10619432

12. Yao Z, Shafer OT. The Drosophila Circadian Clock Is a Variably Coupled Network of Multiple Peptidergic Units. Science. 2014;343(6178):1516–20. doi: 10.1126/science.1251285 24675961

13. Mertens I, Vandingenen A, Johnson EC, Shafer OT, Li W, Trigg JS, et al. PDF receptor signaling in Drosophila contributes to both circadian and geotactic behaviors. Neuron. 2005;48(2):213–9. doi: 10.1016/j.neuron.2005.09.009 WOS:000232838700011. 16242402

14. Lear BC, Lin JM, Keath JR, McGill JJ, Raman IM, Allada R. The ion channel narrow abdomen is critical for neural output of the Drosophila circadian pacemaker. Neuron. 2005;48(6):965–76. doi: 10.1016/j.neuron.2005.10.030 WOS:000234301700012. 16364900

15. Hyun S, Lee Y, Hong ST, Bang S, Paik D, Kang JK, et al. Drosophila GPCR Han is a receptor for the circadian clock neuropeptide PDF. Neuron. 2005;48(2):267–78. doi: 10.1016/j.neuron.2005.08.025 WOS:000232838700016. 16242407

16. Shafer OT, Yao Z. Pigment-Dispersing Factor Signaling and Circadian Rhythms in Insect Locomotor Activity. Current opinion in insect science. 2014;1:73–80. doi: 10.1016/j.cois.2014.05.002 25386391; PubMed Central PMCID: PMC4224320.

17. Li Y, Guo F, Shen J, Rosbash M. PDF and cAMP enhance PER stability in Drosophila clock neurons. Proc Natl Acad Sci U S A. 2014;111(13):E1284–90. doi: 10.1073/pnas.1402562111 24707054; PubMed Central PMCID: PMC3977231.

18. Seluzicki A, Flourakis M, Kula-Eversole E, Zhang L, Kilman V, Allada R. Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior. Plos Biol. 2014;12(3):e1001810. doi: 10.1371/journal.pbio.1001810 24643294; PubMed Central PMCID: PMC3958333.

19. Blau J, Young MW. Cycling vrille expression is required for a functional Drosophila clock. Cell. 1999;99(6):661–71. doi: 10.1016/s0092-8674(00)81554-8 10612401.

20. Park JH, Helfrich-Forster C, Lee G, Liu L, Rosbash M, Hall JC. Differential regulation of circadian pacemaker output by separate clock genes in Drosophila. Proc Natl Acad Sci U S A. 2000;97(7):3608–13. doi: 10.1073/pnas.070036197 10725392; PubMed Central PMCID: PMC16287.

21. Mezan S, Feuz JD, Deplancke B, Kadener S. PDF Signaling Is an Integral Part of the Drosophila Circadian Molecular Oscillator. Cell Rep. 2016;17(3):708–19. doi: 10.1016/j.celrep.2016.09.048 27732848; PubMed Central PMCID: PMC5081397.

22. Gunawardhana KL, Hardin PE. VRILLE Controls PDF Neuropeptide Accumulation and Arborization Rhythms in Small Ventrolateral Neurons to Drive Rhythmic Behavior in Drosophila. Curr Biol. 2017;27(22):3442–53 e4. doi: 10.1016/j.cub.2017.10.010 29103936.

23. Ruhf ML, Braun A, Papoulas O, Tamkun JW, Randsholt N, Meister M. The domino gene of Drosophila encodes novel members of the SW12/SNF2 family of DNA-dependent ATPases, which contribute to the silencing of homeotic genes. Development. 2001;128(8):1429–41. WOS:000168498900019. 11262242

24. Kusch T, Florens L, MacDonald WH, Swanson SK, Glaser RL, Yates JR, et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science. 2004;306(5704):2084–7. doi: 10.1126/science.1103455 WOS:000225841000060. 15528408

25. Borner K, Becker PB. Splice variants of the SWR1-type nucleosome remodeling factor Domino have distinct functions during Drosophila melanogaster oogenesis. Development. 2016;143(17):3154–67. doi: 10.1242/dev.139634 27578180.

26. Tea JS, Luo LQ. The chromatin remodeling factor Bap55 functions through the TIP60 complex to regulate olfactory projection neuron dendrite targeting. Neural Development. 2011;6. Artn 510.1186/1749-8104-6-5. WOS:000290529200002.

27. Rust K, Tiwari MD, Mishra VK, Grawe F, Wodarz A. Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila. Embo J. 2018. doi: 10.15252/embj.201798659 29997178.

28. Dubruille R, Murad A, Rosbash M, Emery P. A Constant Light-Genetic Screen Identifies KISMET as a Regulator of Circadian Photoresponses. Plos Genetics. 2009;5(12). ARTN e1000787 10.1371/journal.pgen.1000787. WOS:000273469700037.

29. Kwok RS, Lam VH, Chiu JC. Understanding the role of chromatin remodeling in the regulation of circadian transcription in Drosophila. Fly. 2015;9(4):145–54. doi: 10.1080/19336934.2016.1143993 WOS:000375037400001. 26926115

30. Adewoye AB, Kyriacou CP, Tauber E. Identification and functional analysis of early gene expression induced by circadian light-resetting in Drosophila. Bmc Genomics. 2015;16. ARTN 570 10.1186/s12864-015-1787-7. WOS:000358760600005.

31. Kwok RS, Li YH, Lei AJ, Edery I, Chiu JC. The Catalytic and Non-catalytic Functions of the Brahma Chromatin-Remodeling Protein Collaborate to Fine-Tune Circadian Transcription in Drosophila. PLoS genetics. 2015;11(7):e1005307. doi: 10.1371/journal.pgen.1005307 26132408; PubMed Central PMCID: PMC4488936.

32. Choi H, Larsen B, Lin ZY, Breitkreutz A, Mellacheruvu D, Fermin D, et al. SAINT: probabilistic scoring of affinity purification-mass spectrometry data. Nature methods. 2011;8(1):70–3. doi: 10.1038/nmeth.1541 21131968; PubMed Central PMCID: PMC3064265.

33. Kula-Eversole E, Nagoshi E, Shang YH, Rodriguez J, Allada R, Rosbash M. Surprising gene expression patterns within and between PDF-containing circadian neurons in Drosophila. P Natl Acad Sci USA. 2010;107(30):13497–502. doi: 10.1073/pnas.1002081107 WOS:000280602800056. 20624977

34. Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature. 2007;448(7150):151–U1. doi: 10.1038/nature05954 WOS:000247934500033. 17625558

35. Zhang XY, Lu K, Zhou JL, Zhou Q. Molecular characterization and gene functional analysis of Dicer-2 gene from Nilaparvata lugens (Hemiptera: Geometroidea). Insect Science. 2013;20(1):61–8. doi: 10.1111/j.1744-7917.2012.01539.x WOS:000313988600007. 23955826

36. Kaneko M, Hall JC. Neuroanatomy of cells expressing clock genes in Drosophila: Transgenic manipulation of the period and timeless genes to mark the perikarya of circadian pacemaker neurons and their projections. Journal of Comparative Neurology. 2000;422(1):66–94. doi: 10.1002/(sici)1096-9861(20000619)422:1<66::aid-cne5>3.0.co;2-2 WOS:000087240900005. 10842219

37. Abruzzi KC, Rodriguez J, Menet JS, Desrochers J, Zadina A, Luo W, et al. Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression. Genes Dev. 2011;25(22):2374–86. doi: 10.1101/gad.174110.111 10.1101/gad.178079.111. 22085964; PubMed Central PMCID: PMC3222903.

38. Mahesh G, Jeong E, Ng FS, Liu Y, Gunawardhana K, Houl JH, et al. Phosphorylation of the transcription activator CLOCK regulates progression through a approximately 24-h feedback loop to influence the circadian period in Drosophila. The Journal of biological chemistry. 2014;289(28):19681–93. doi: 10.1074/jbc.M114.568493 24872414; PubMed Central PMCID: PMC4094078.

39. Veleri S, Rieger D, Helfrich-Forster C, Stanewsky R. Hofbauer-Buchner eyelet affects circadian photosensitivity and coordinates TIM and PER expression in Drosophila clock neurons. Journal of Biological Rhythms. 2007;22(1):29–42. doi: 10.1177/0748730406295754 WOS:000243489800004. 17229923

40. Agrawal P, Hardin PE. The Drosophila Receptor Protein Tyrosine Phosphatase LAR Is Required for Development of Circadian Pacemaker Neuron Processes That Support Rhythmic Activity in Constant Darkness But Not during Light/Dark Cycles. J Neurosci. 2016;36(13):3860–70. doi: 10.1523/JNEUROSCI.4523-15.2016 27030770; PubMed Central PMCID: PMC4812141.

41. McGuire SE, Roman G, Davis RL. Gene expression systems in Drosophila: a synthesis of time and space. Trends in Genetics. 2004;20(8):384–91. doi: 10.1016/j.tig.2004.06.012 WOS:000223238900011. 15262411

42. Choi C, Fortin JP, McCarthy EV, Oksman L, Kopin AS, Nitabach MN. Cellular Dissection of Circadian Peptide Signals with Genetically Encoded Membrane-Tethered Ligands. Current Biology. 2009;19(14):1167–75. doi: 10.1016/j.cub.2009.06.029 WOS:000268530200022. 19592252

43. Renn SC, Park JH, Rosbash M, Hall JC, Taghert PH. A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell. 1999;99(7):791–802. doi: 10.1016/s0092-8674(00)81676-1 10619432.

44. Liu K, Ding L, Li Y, Yang H, Zhao C, Lei Y, et al. Neuronal necrosis is regulated by a conserved chromatin-modifying cascade. Proc Natl Acad Sci U S A. 2014;111(38):13960–5. doi: 10.1073/pnas.1413644111 25201987; PubMed Central PMCID: PMC4183342.

45. Pirooznia SK, Sarthi J, Johnson AA, Toth MS, Chiu K, Koduri S, et al. Tip60 HAT Activity Mediates APP Induced Lethality and Apoptotic Cell Death in the CNS of a Drosophila Alzheimer's Disease Model. Plos One. 2012;7(7). ARTN e41776 10.1371/journal.pone.0041776. WOS:000309240600047.

46. Guo F, Cerullo I, Chen X, Rosbash M. PDF neuron firing phase-shifts key circadian activity neurons in Drosophila. Elife. 2014;3. doi: 10.7554/eLife.02780 24939987; PubMed Central PMCID: PMC4092873.

47. Murad A, Emery-Le M, Emery P. A subset of dorsal neurons modulates circadian behavior and light responses in Drosophila. Neuron. 2007;53(5):689–701. doi: 10.1016/j.neuron.2007.01.034 WOS:000245127100010. 17329209

48. Grima B, Lamouroux A, Chelot E, Papin C, Limbourg-Bouchon B, Rouyer F. The F-box protein Slimb controls the levels of clock proteins Period and Timeless. Nature. 2002;420(6912):178–82. doi: 10.1038/nature01122 WOS:000179200900046. 12432393

49. Levine JD, Funes P, Dowse HB, Hall JC. Signal analysis of behavioral and molecular cycles. BMC Neurosci. 2002;3:1. doi: 10.1186/1471-2202-3-1 11825337; PubMed Central PMCID: PMC65508.

50. Zhang Y, Ling J, Yuan C, Dubruille R, Emery P. A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science. 2013;340(6134):879–82. doi: 10.1126/science.1234746 23687048; PubMed Central PMCID: PMC4078874.

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