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Edited by Terry L. Orr-Weaver, Whitehead Institute, Cambridge, MA, and approved November 17, 2014 (received for review October 4, 2014)
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.
Footnotes
↵1Present address: Yale Medical School, Department of Cellular and Molecular Physiology, New Haven, CT 06510.
↵2Present address: Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children and Harvard Medical School, Boston, MA 024114.
↵3Present address: Wellstone Program, Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655.
- ↵4To whom correspondence should be addressed. Email: mlilly{at}helix.nih.gov.
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.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1419156112/-/DCSupplemental.
Iml1/GATOR1 controls meiotic entry in Drosophila
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