Ecdysone acts through cortex glia to regulate sleep in Drosophila

  1. Yongjun Li
  2. Paula Haynes
  3. Shirley L Zhang
  4. Zhifeng Yue
  5. Amita Sehgal  Is a corresponding author
  1. Howard Hughes Medical Institute, University of Pennsylvania, United States

Abstract

Steroid hormones are attractive candidates for transmitting long-range signals to affect behavior. These lipid-soluble molecules derived from dietary cholesterol easily penetrate the brain and act through nuclear hormone receptors (NHRs) that function as transcription factors. To determine the extent to which NHRs affect sleep: wake cycles, we knocked down each of the 18 highly conserved NHRs found in Drosophila adults and report that the ecdysone receptor (EcR) and its direct downstream NHR Eip75B (E75) act in glia to regulate the rhythm and amount of sleep. Given that ecdysone synthesis genes have little to no expression in the fly brain, ecdysone appears to act as a long-distance signal and our data suggest that it enters the brain more at night. Anti-EcR staining localizes to the cortex glia in the brain and functional screening of glial subtypes revealed that EcR functions in adult cortex glia to affect sleep. Cortex glia are implicated in lipid metabolism, which appears to be relevant for actions of ecdysone as ecdysone treatment mobilizes lipid droplets, and knockdown of glial EcR results in more lipid droplets. In addition, sleep-promoting effects of exogenous ecdysone are diminished in lsd-2 mutant flies, which are lean and deficient in lipid accumulation. We propose that ecdysone is a systemic secreted factor that modulates sleep by stimulating lipid metabolism in cortex glia.

Data availability

All data analyzed and reported in this study are included in the manuscript, supplementary tables, and source data linked to figures.

Article and author information

Author details

  1. Yongjun Li

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Paula Haynes

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Shirley L Zhang

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6672-2044
  4. Zhifeng Yue

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amita Sehgal

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    For correspondence
    amita@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7354-9641

Funding

Howard Hughes Medical Institute

  • Amita Sehgal

National Institute of Neurological Disorders and Stroke (R01NS048471)

  • Amita Sehgal

National Institutes of Health (R01DK120757)

  • Amita Sehgal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,685
    views
  • 406
    downloads
  • 18
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Yongjun Li
  2. Paula Haynes
  3. Shirley L Zhang
  4. Zhifeng Yue
  5. Amita Sehgal
(2023)
Ecdysone acts through cortex glia to regulate sleep in Drosophila
eLife 12:e81723.
https://doi.org/10.7554/eLife.81723

Share this article

https://doi.org/10.7554/eLife.81723

Further reading

    1. Genetics and Genomics
    2. Neuroscience
    Martina Rudgalvyte, Zehan Hu ... Dominique A Glauser
    Research Article

    Thermal nociception in Caenorhabditis elegans is regulated by the Ca²+/calmodulin-dependent protein kinase CMK-1, but its downstream effectors have remained unclear. Here, we combined in vitro kinase assays with mass-spectrometry-based phosphoproteomics to identify hundreds of CMK-1 substrates, including the calcineurin A subunit TAX-6, phosphorylated within its conserved regulatory domain. Genetic and pharmacological analyses reveal multiple antagonistic interactions between CMK-1 and calcineurin signaling in modulating both naive thermal responsiveness and adaptation to repeated noxious stimuli. Cell-specific manipulations indicate that CMK-1 acts in AFD and ASER thermo-sensory neurons, while TAX-6 functions in FLP thermo-sensory neurons and downstream interneurons. Since CMK-1 and TAX-6 act in distinct cell types, the phosphorylation observed in vitro might not directly underlie the behavioral phenotype. Instead, the opposing effects seem to arise from their distributed roles within the sensory circuit. Overall, our study provides (1) a resource of candidate CMK-1 targets for further dissecting CaM kinase signaling and (2) evidence of a previously unrecognized, circuit-level antagonism between CMK-1 and calcineurin pathways. These findings highlight a complex interplay of signaling modules that modulate thermal nociception and adaptation, offering new insights into potentially conserved mechanisms that shape nociceptive plasticity and pain (de)sensitization in more complex nervous systems.

    1. Genetics and Genomics
    Mengjia Li, Hengchao Zhang ... Lixiang Chen
    Research Article

    Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that can modulate cellular metabolism, epigenetic modification, and redox homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be associated with pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains unclear. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We found that knockdown IDH1 induced chromatin reorganization and subsequently led to abnormalities biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of α-ketoglutarate (α-KG).We further revealed that knockdown IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq, and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies.