Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity

  1. Jason W Millington
  2. George P Brownrigg
  3. Charlotte Chao
  4. Ziwei Sun
  5. Paige J Basner-Collins
  6. Lianna W Wat
  7. Bruno Hudry
  8. Irene Miguel-Aliaga
  9. Elizabeth J Rideout  Is a corresponding author
  1. The University of British Columbia, Canada
  2. Universite Nice Sophia Antipolis, France
  3. Imperial College London, United Kingdom

Abstract

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed that body size plasticity was higher in females, yet the mechanisms underlying increased female body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-biased increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This sex-biased upregulation of IIS activity was triggered by a diet-induced increase in stunted mRNA in females, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination gene transformer promotes the diet-induced increase in stunted mRNA via transcriptional coactivator Spargel to regulate the male-female difference in body size plasticity. Together, these findings provide vital insight into conserved mechanisms underlying the sex difference in nutrient-dependent body size plasticity.

Data availability

All data generated in this study are provided in supplementary file 2. All statistical tests and p-values are listed in supplementary file 1. Exact diets used in this study are described in supplementary file 3 for ease of replication. All genotypes used in this study are listed in supplementary file 4. A complete list of primers used in this study is provided in supplementary file 5

Article and author information

Author details

  1. Jason W Millington

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. George P Brownrigg

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Charlotte Chao

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Ziwei Sun

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Paige J Basner-Collins

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Lianna W Wat

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Bruno Hudry

    Faculte des Sciences, Universite Nice Sophia Antipolis, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Irene Miguel-Aliaga

    Faculty of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Elizabeth J Rideout

    Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, Canada
    For correspondence
    elizabeth.rideout@ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0012-2828

Funding

Canadian Institutes of Health Research (PJT-153072)

  • Elizabeth J Rideout

Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-04249)

  • Elizabeth J Rideout

Michael Smith Foundation for Health Research (16876)

  • Elizabeth J Rideout

Canada Foundation for Innovation (JELF-34879)

  • Elizabeth J Rideout

H2020 European Research Council (ERCAdG787470)

  • Irene Miguel-Aliaga

European Molecular Biology Organization (aALTF782-2015)

  • Bruno Hudry

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

Reviewing Editor

  1. Jiwon Shim, Hanyang University, Republic of Korea

Version history

  1. Received: April 28, 2020
  2. Accepted: January 11, 2021
  3. Accepted Manuscript published: January 15, 2021 (version 1)
  4. Version of Record published: February 5, 2021 (version 2)

Copyright

© 2021, Millington 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

  • 3,245
    Page views
  • 462
    Downloads
  • 21
    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. Jason W Millington
  2. George P Brownrigg
  3. Charlotte Chao
  4. Ziwei Sun
  5. Paige J Basner-Collins
  6. Lianna W Wat
  7. Bruno Hudry
  8. Irene Miguel-Aliaga
  9. Elizabeth J Rideout
(2021)
Female-biased upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity
eLife 10:e58341.
https://doi.org/10.7554/eLife.58341

Share this article

https://doi.org/10.7554/eLife.58341

Further reading

    1. Developmental Biology
    2. Neuroscience
    Kristine B Walhovd, Stine K Krogsrud ... Didac Vidal-Pineiro
    Research Article

    Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article Updated

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.