The E3 Ubiquitin Ligase Adaptor Links the Core Circadian Clock to Neuropeptide and Behavioral Rhythms

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Nov 20

PMID 34799448

Citations 5

Authors

Jongbin Lee

Chunghun Lim

Tae Hee Han

Tomas Andreani

Matthew Moye

Jack Curran

Eric Johnson

William L Kath

Casey O Diekman

Bridget C Lear

Ravi Allada

Affiliations

Soon will be listed here.

Abstract

Circadian transcriptional timekeepers in pacemaker neurons drive profound daily rhythms in sleep and wake. Here we reveal a molecular pathway that links core transcriptional oscillators to neuronal and behavioral rhythms. Using two independent genetic screens, we identified mutants of () with poor behavioral rhythmicity. expression in pacemaker neurons expressing the neuropeptide PIGMENT-DISPERSING FACTOR (PDF) is required for robust rhythms. Loss of results in elevated PDF accumulation in nerve terminals even in mutants lacking a functional core clock. TANGO10 protein itself is rhythmically expressed in PDF terminals. Mass spectrometry of TANGO10 complexes reveals interactions with the E3 ubiquitin ligase CULLIN 3 (CUL3). CUL3 depletion phenocopies mutant effects on PDF even in the absence of the core clock gene Patch clamp electrophysiology in mutant neurons demonstrates elevated spontaneous firing potentially due to reduced voltage-gated Shaker-like potassium currents. We propose that transduces molecular oscillations from the core clock to neuropeptide release important for behavioral rhythms.

Citing Articles

A circadian clock output functions independently of phyB to sustain daytime PIF3 degradation.

Liu W, Lowrey H, Xu A, Leung C, Adamchek C, He J Proc Natl Acad Sci U S A. 2024; 121(35):e2408322121.

PMID: 39163340 PMC: 11363348. DOI: 10.1073/pnas.2408322121.

Reanalysis of primate brain circadian transcriptomics reveals connectivity-related oscillations.

Lee J, Chen S, Monfared R, Derdeyn P, Leong K, Chang T iScience. 2023; 26(10):107810.

PMID: 37752952 PMC: 10518731. DOI: 10.1016/j.isci.2023.107810.

Nonlinear expression patterns and multiple shifts in gene network interactions underlie robust phenotypic change in Drosophila melanogaster selected for night sleep duration.

Souto-Maior C, Serrano Negron Y, Harbison S PLoS Comput Biol. 2023; 19(8):e1011389.

PMID: 37561813 PMC: 10443883. DOI: 10.1371/journal.pcbi.1011389.

Mutation of the Drosophila melanogaster serotonin transporter dSERT impacts sleep, courtship, and feeding behaviors.

Knapp E, Kaiser A, Arnold R, Sampson M, Ruppert M, Xu L PLoS Genet. 2022; 18(11):e1010289.

PMID: 36409783 PMC: 9721485. DOI: 10.1371/journal.pgen.1010289.

Death of a Protein: The Role of E3 Ubiquitin Ligases in Circadian Rhythms of Mice and Flies.

Abdalla O, Mascarenhas B, Cheng H Int J Mol Sci. 2022; 23(18).

PMID: 36142478 PMC: 9502492. DOI: 10.3390/ijms231810569.

References

Rideout E, Dornan A, Neville M, Eadie S, Goodwin S . Control of sexual differentiation and behavior by the doublesex gene in Drosophila melanogaster. Nat Neurosci. 2010; 13(4):458-66. PMC: 3092424. DOI: 10.1038/nn.2515. View

Ceriani M, Hogenesch J, Yanovsky M, Panda S, Straume M, Kay S . Genome-wide expression analysis in Drosophila reveals genes controlling circadian behavior. J Neurosci. 2002; 22(21):9305-19. PMC: 6758054. View

Foot N, Henshall T, Kumar S . Ubiquitination and the Regulation of Membrane Proteins. Physiol Rev. 2016; 97(1):253-281. DOI: 10.1152/physrev.00012.2016. View

Gschweitl M, Ulbricht A, Barnes C, Enchev R, Stoffel-Studer I, Meyer-Schaller N . A SPOPL/Cullin-3 ubiquitin ligase complex regulates endocytic trafficking by targeting EPS15 at endosomes. Elife. 2016; 5:e13841. PMC: 4846373. DOI: 10.7554/eLife.13841. View

Grima B, Dognon A, Lamouroux A, Chelot E, Rouyer F . CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock. PLoS Biol. 2012; 10(8):e1001367. PMC: 3413713. DOI: 10.1371/journal.pbio.1001367. View

Kula-Eversole E, Nagoshi E, Shang Y, Rodriguez J, Allada R, Rosbash M . Surprising gene expression patterns within and between PDF-containing circadian neurons in Drosophila. Proc Natl Acad Sci U S A. 2010; 107(30):13497-502. PMC: 2922133. DOI: 10.1073/pnas.1002081107. View

Zhang L, Chung B, Lear B, Kilman V, Liu Y, Mahesh G . DN1(p) circadian neurons coordinate acute light and PDF inputs to produce robust daily behavior in Drosophila. Curr Biol. 2010; 20(7):591-9. PMC: 2864127. DOI: 10.1016/j.cub.2010.02.056. View

Lin Y, Stormo G, Taghert P . The neuropeptide pigment-dispersing factor coordinates pacemaker interactions in the Drosophila circadian system. J Neurosci. 2004; 24(36):7951-7. PMC: 6729918. DOI: 10.1523/JNEUROSCI.2370-04.2004. View

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. View

10.

Sivachenko A, Li Y, Abruzzi K, Rosbash M . The transcription factor Mef2 links the Drosophila core clock to Fas2, neuronal morphology, and circadian behavior. Neuron. 2013; 79(2):281-92. PMC: 3859024. DOI: 10.1016/j.neuron.2013.05.015. View

11.

Hermanstyne T, Granados-Fuentes D, Mellor R, Herzog E, Nerbonne J . Acute Knockdown of Kv4.1 Regulates Repetitive Firing Rates and Clock Gene Expression in the Suprachiasmatic Nucleus and Daily Rhythms in Locomotor Behavior. eNeuro. 2017; 4(3). PMC: 5440767. DOI: 10.1523/ENEURO.0377-16.2017. View

12.

Peschel N, Veleri S, Stanewsky R . Veela defines a molecular link between Cryptochrome and Timeless in the light-input pathway to Drosophila's circadian clock. Proc Natl Acad Sci U S A. 2006; 103(46):17313-8. PMC: 1859927. DOI: 10.1073/pnas.0606675103. View

13.

Krashes M, Keene A, Leung B, Armstrong J, Waddell S . Sequential use of mushroom body neuron subsets during drosophila odor memory processing. Neuron. 2007; 53(1):103-15. PMC: 1828290. DOI: 10.1016/j.neuron.2006.11.021. View

14.

Tricoire H, Battisti V, Trannoy S, Lasbleiz C, Pret A, Monnier V . The steroid hormone receptor EcR finely modulates Drosophila lifespan during adulthood in a sex-specific manner. Mech Ageing Dev. 2009; 130(8):547-52. DOI: 10.1016/j.mad.2009.05.004. View

15.

Diekman C, Belle M, Irwin R, Allen C, Piggins H, Forger D . Causes and consequences of hyperexcitation in central clock neurons. PLoS Comput Biol. 2013; 9(8):e1003196. PMC: 3749949. DOI: 10.1371/journal.pcbi.1003196. View

16.

Richier B, Michard-Vanhee C, Lamouroux A, Papin C, Rouyer F . The clockwork orange Drosophila protein functions as both an activator and a repressor of clock gene expression. J Biol Rhythms. 2008; 23(2):103-16. DOI: 10.1177/0748730407313817. View

17.

Barbagallo B, Prescott H, Boyle P, Climer J, Francis M . A dominant mutation in a neuronal acetylcholine receptor subunit leads to motor neuron degeneration in Caenorhabditis elegans. J Neurosci. 2010; 30(42):13932-42. PMC: 2965043. DOI: 10.1523/JNEUROSCI.1515-10.2010. View

18.

Lin D, Goodman C . Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance. Neuron. 1994; 13(3):507-23. DOI: 10.1016/0896-6273(94)90022-1. View

19.

Lim C, Chung B, Pitman J, McGill J, Pradhan S, Lee J . Clockwork orange encodes a transcriptional repressor important for circadian-clock amplitude in Drosophila. Curr Biol. 2007; 17(12):1082-9. PMC: 1963421. DOI: 10.1016/j.cub.2007.05.039. View

20.

Gunawardhana K, Hardin P . VRILLE Controls PDF Neuropeptide Accumulation and Arborization Rhythms in Small Ventrolateral Neurons to Drive Rhythmic Behavior in Drosophila. Curr Biol. 2017; 27(22):3442-3453.e4. DOI: 10.1016/j.cub.2017.10.010. View