TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila

Edited by Terry L. Orr-Weaver, Whitehead Institute, Cambridge, MA, and approved November 17, 2014 (received for review October 4, 2014)
December 15, 2014
111 (52) E5670-E5677

Significance

The target of rapamycin complex 1 (TORC1) promotes cell growth and anabolic metabolism. In yeast, entry into meiosis is contingent on the down-regulation of TORC1 activity by the increased minichromosome loss 1/GTPase-activating proteins toward Rags 1 (Iml1/GATOR1) complex in response to amino acid starvation. Here we define the developmental requirements for the TORC1 regulators Iml1/GATOR1 and GATOR2 during Drosophila oogenesis. We demonstrate that, as is observed in yeast, the Iml1/GATOR1 complex down-regulates TORC1 activity to facilitate the mitotic/meiotic transition in Drosophila ovarian cysts. Later in oogenesis, components of the GATOR2 complex oppose the activity of GATOR1 to enable a rise in TORC1 activity that drives oocyte development and growth. Thus, a conserved nutrient stress pathway has been incorporated into a developmental program that regulates meiotic progression in Drosophila.

Abstract

In single-cell eukaryotes the pathways that monitor nutrient availability are central to initiating the meiotic program and gametogenesis. In Saccharomyces cerevisiae an essential step in the transition to the meiotic cycle is the down-regulation of the nutrient-sensitive target of rapamycin complex 1 (TORC1) by the increased minichromosome loss 1/ GTPase-activating proteins toward Rags 1 (Iml1/GATOR1) complex in response to amino acid starvation. How metabolic inputs influence early meiotic progression and gametogenesis remains poorly understood in metazoans. Here we define opposing functions for the TORC1 regulatory complexes Iml1/GATOR1 and GATOR2 during Drosophila oogenesis. We demonstrate that, as is observed in yeast, the Iml1/GATOR1 complex inhibits TORC1 activity to slow cellular metabolism and drive the mitotic/meiotic transition in developing ovarian cysts. In iml1 germline depletions, ovarian cysts undergo an extra mitotic division before meiotic entry. The TORC1 inhibitor rapamycin can suppress this extra mitotic division. Thus, high TORC1 activity delays the mitotic/meiotic transition. Conversely, mutations in Tor, which encodes the catalytic subunit of the TORC1 complex, result in premature meiotic entry. Later in oogenesis, the GATOR2 components Mio and Seh1 are required to oppose Iml1/GATOR1 activity to prevent the constitutive inhibition of TORC1 and a block to oocyte growth and development. To our knowledge, these studies represent the first examination of the regulatory relationship between the Iml1/GATOR1 and GATOR2 complexes within the context of a multicellular organism. Our data imply that the central role of the Iml1/GATOR1 complex in the regulation of TORC1 activity in the early meiotic cycle has been conserved from single cell to multicellular organisms.

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Acknowledgments

We thank Aurello Teleman, Thomas Neufeld, Eric Baehrecke, and Helmut Kramer for providing reagents and the Transgenic RNAi Project at Harvard Medical School [supported by National Institutes of Health (NIH)/National Institute of General Medical Sciences Grant R01-GM084947] for providing transgenic RNAi plasmid vectors used in this study. Some stocks used in this study were obtained from the Bloomington Drosophila Stock Center (supported by NIH Grant P40OD018537). This work was supported by Grant ZIA HD001613 16 from the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 111 | No. 52
December 30, 2014
PubMed: 25512509

Classifications

Submission history

Published online: December 15, 2014
Published in issue: December 30, 2014

Keywords

  1. meiosis
  2. Iml1
  3. GATOR1
  4. GATOR2
  5. Drosophila

Acknowledgments

We thank Aurello Teleman, Thomas Neufeld, Eric Baehrecke, and Helmut Kramer for providing reagents and the Transgenic RNAi Project at Harvard Medical School [supported by National Institutes of Health (NIH)/National Institute of General Medical Sciences Grant R01-GM084947] for providing transgenic RNAi plasmid vectors used in this study. Some stocks used in this study were obtained from the Bloomington Drosophila Stock Center (supported by NIH Grant P40OD018537). This work was supported by Grant ZIA HD001613 16 from the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Youheng Wei
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Brad Reveal
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
John Reich
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Willem J. Laursen
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Present address: Yale Medical School, Department of Cellular and Molecular Physiology, New Haven, CT 06510.
Stefania Senger
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Present address: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA 024114.
Tanveer Akbar
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Takako Iida-Jones
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Present address: Wellstone Program, Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.
Weili Cai
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Michal Jarnik
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
Mary A. Lilly4 [email protected]
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Notes

4
To whom correspondence should be addressed. Email: [email protected].
Author contributions: Y.W., B.R., J.R., W.J.L., S.S., T.A., T.I.-J., W.C., and M.A.L. designed research; Y.W., B.R., J.R., W.J.L., T.A., W.C., and M.J. performed research; B.R., S.S., T.A., and T.I.-J. contributed new reagents/analytic tools; Y.W., B.R., J.R., W.J.L., T.A., W.C., M.J., and M.A.L. analyzed data; and Y.W. and M.A.L. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila
    Proceedings of the National Academy of Sciences
    • Vol. 111
    • No. 52
    • pp. 18401-18799

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