The GATOR complex regulates an essential response to meiotic double-stranded breaks in Drosophila

  1. Youheng Wei
  2. Lucia Bettedi
  3. Chun-Yuan Ting
  4. Kuikwon Kim
  5. Yingbiao Zhang
  6. Jiadong Cai
  7. Mary A Lilly  Is a corresponding author
  1. National Institute of Child Health and Human Development, National Institutes of Health, United States
  2. Yangzhou University, China

Abstract

The TORC1 regulator GATOR1/SEACIT controls meiotic entry and early meiotic events in yeast. However, how metabolic pathways influence meiotic progression in metazoans remains poorly understood. Here we examine the role of the TORC1 regulators GATOR1 and GATOR2 in the response to meiotic double-stranded breaks (DSB) during Drosophila oogenesis. We find that in mutants of the GATOR2 component mio, meiotic DSBs trigger the constitutive downregulation of TORC1 activity and a permanent arrest in oocyte growth. Conversely, in GATOR1 mutants, high TORC1 activity results in the delayed repair of meiotic DSBs and the hyperactivation of p53. Unexpectedly, we found that GATOR1 inhibits retrotransposon expression in the presence of meiotic DSBs in a pathway that functions in parallel to p53. Thus, our studies have revealed a link between oocyte metabolism, the repair of meiotic DSBs and retrotransposon expression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Youheng Wei

    Cell Biology and Structural Biology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lucia Bettedi

    Cell Biology and Structural Biology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chun-Yuan Ting

    Cell Biology and Structural Biology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2302-4203
  4. Kuikwon Kim

    Cell Biology and Structural Biology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yingbiao Zhang

    Cell Biology and Structural Biology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiadong Cai

    College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Mary A Lilly

    Cell Biology and Structural Biology Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
    For correspondence
    lillym@helix.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1564-619X

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (Intramural Program HD00163 16)

  • Mary A Lilly

National Science Foundation of Jiangsu Province (BK20181456)

  • Youheng Wei

National Natural Science Foundation of China (31872287)

  • Youheng Wei

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

Reviewing Editor

  1. Bruce Edgar, University of Utah, United States

Version history

  1. Received: September 18, 2018
  2. Accepted: October 13, 2019
  3. Accepted Manuscript published: October 25, 2019 (version 1)
  4. Version of Record published: November 6, 2019 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 2,563
    Page views
  • 297
    Downloads
  • 11
    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. Youheng Wei
  2. Lucia Bettedi
  3. Chun-Yuan Ting
  4. Kuikwon Kim
  5. Yingbiao Zhang
  6. Jiadong Cai
  7. Mary A Lilly
(2019)
The GATOR complex regulates an essential response to meiotic double-stranded breaks in Drosophila
eLife 8:e42149.
https://doi.org/10.7554/eLife.42149

Share this article

https://doi.org/10.7554/eLife.42149

Further reading

    1. Developmental Biology
    2. Neuroscience
    Tariq Zaman, Daniel Vogt ... Michael R Williams
    Research Article

    The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.

    1. Developmental Biology
    2. Neuroscience
    Smrithi Prem, Bharati Dev ... Emanuel DiCicco-Bloom
    Research Article

    Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.