insomniac links the development and function of a sleep regulatory circuit

  1. Qiuling Li
  2. Hyunsoo Jang
  3. Kayla Y Lim
  4. Alexie Lessing
  5. Nicholas Stavropoulos  Is a corresponding author
  1. New York University School of Medicine, United States
  2. Rutgers University, United States

Abstract

Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here we show that Insomniac (Inc), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila. The loss of inc causes structural and functional alterations within the mushroom body, a center for sensory integration, associative learning, and sleep regulation. In inc mutants, mushroom body neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders.

Data availability

Data for all figures and code used to analyze sleep are included in the supporting files.

Article and author information

Author details

  1. Qiuling Li

    Department of Neuroscience and Physiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hyunsoo Jang

    Department of Neuroscience and Physiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9191-3697
  3. Kayla Y Lim

    Department of Neuroscience and Physiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alexie Lessing

    Department of Neuroscience and Physiology, New York University School of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2044-7822
  5. Nicholas Stavropoulos

    Waksman Institute, Rutgers University, Piscataway, United States
    For correspondence
    stavropoulos@waksman.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5915-2760

Funding

Howard Hughes Medical Institute (International Student Research Fellowship)

  • Qiuling Li

Irma T. Hirschl Trust (Career Scientist Award)

  • Nicholas Stavropoulos

National Institute of Neurological Disorders and Stroke (R01NS112844)

  • Nicholas Stavropoulos

National Institute of Neurological Disorders and Stroke (R21NS111304)

  • Nicholas Stavropoulos

G. Harold and Leila Y. Mathers Foundation

  • Nicholas Stavropoulos

Whitehall Foundation (2013-05-78)

  • Nicholas Stavropoulos

Alfred P. Sloan Foundation

  • Nicholas Stavropoulos

Leon Levy Foundation

  • Nicholas Stavropoulos

Brain and Behavior Research Foundation (NARSAD Young Investigator)

  • Nicholas Stavropoulos

Sleep Research Society Foundation (J. Christian Gillin,M.D. Research Award)

  • Nicholas Stavropoulos

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

Reviewing Editor

  1. Ronald L Calabrese, Emory University, United States

Publication history

  1. Received: December 4, 2020
  2. Accepted: October 15, 2021
  3. Accepted Manuscript published: December 15, 2021 (version 1)
  4. Accepted Manuscript updated: December 16, 2021 (version 2)
  5. Version of Record published: January 13, 2022 (version 3)

Copyright

© 2021, 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

  • 1,353
    Page views
  • 191
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Qiuling Li
  2. Hyunsoo Jang
  3. Kayla Y Lim
  4. Alexie Lessing
  5. Nicholas Stavropoulos
(2021)
insomniac links the development and function of a sleep regulatory circuit
eLife 10:e65437.
https://doi.org/10.7554/eLife.65437

Further reading

    1. Cell Biology
    2. Developmental Biology
    Yalda Afshar, Feyiang Ma ... Luisa Iruela-Arispe
    Research Article

    Environmental cues, such as physical forces and heterotypic cell interactions play a critical role in cell function, yet their collective contributions to transcriptional changes are unclear. Focusing on human endothelial cells, we performed broad individual sample analysis to identify transcriptional drifts associated with environmental changes that were independent of genetic background. Global gene expression profiling by RNAseq and protein expression by LC-MS directed proteomics distinguished endothelial cells in vivo from genetically matched culture (in vitro) samples. Over 43% of the transcriptome was significantly changed by the in vitro environment. Subjecting cultured cells to long-term shear stress significantly rescued the expression of approximately 17% of genes. Inclusion of heterotypic interactions by co-culture of endothelial cells with smooth muscle cells normalized approximately 9% of the original in vivo signature. We also identified novel flow dependent genes, as well as genes that necessitate heterotypic cell interactions to mimic the in vivo transcriptome. Our findings highlight specific genes and pathways that rely on contextual information for adequate expression from those that are agnostic of such environmental cues.

    1. Developmental Biology
    Jeff Jiajing Zhou, Jin Sun Cho ... Ken WY Cho
    Research Article

    Histone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. Cis-regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation-deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.