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.

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

  • 3,540
    views
  • 500
    downloads
  • 31
    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. 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
    Anastasiia Lozovska, Ana Casaca ... Moises Mallo
    Research Article

    During the trunk to tail transition the mammalian embryo builds the outlets for the intestinal and urogenital tracts, lays down the primordia for the hindlimb and external genitalia, and switches from the epiblast/primitive streak (PS) to the tail bud as the driver of axial extension. Genetic and molecular data indicate that Tgfbr1 is a key regulator of the trunk to tail transition. Tgfbr1 has been shown to control the switch of the neuromesodermal competent cells from the epiblast to the chordoneural hinge to generate the tail bud. We now show that in mouse embryos Tgfbr1 signaling also controls the remodeling of the lateral plate mesoderm (LPM) and of the embryonic endoderm associated with the trunk to tail transition. In the absence of Tgfbr1, the two LPM layers do not converge at the end of the trunk, extending instead as separate layers until the caudal embryonic extremity, and failing to activate markers of primordia for the hindlimb and external genitalia. The vascular remodeling involving the dorsal aorta and the umbilical artery leading to the connection between embryonic and extraembryonic circulation was also affected in the Tgfbr1 mutant embryos. Similar alterations in the LPM and vascular system were also observed in Isl1 null mutants, indicating that this factor acts in the regulatory cascade downstream of Tgfbr1 in LPM-derived tissues. In addition, in the absence of Tgfbr1 the embryonic endoderm fails to expand to form the endodermal cloaca and to extend posteriorly to generate the tail gut. We present evidence suggesting that the remodeling activity of Tgfbr1 in the LPM and endoderm results from the control of the posterior PS fate after its regression during the trunk to tail transition. Our data, together with previously reported observations, place Tgfbr1 at the top of the regulatory processes controlling the trunk to tail transition.

    1. Developmental Biology
    2. Neuroscience
    Odessa R Yabut, Jessica Arela ... Samuel J Pleasure
    Research Article

    Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases and that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.