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Mei-P26 regulates microRNAs and cell growth in the Drosophila ovarian stem cell lineage

Nature volume 454, pages 241–245 (2008)Cite this article

Abstract

Drosophila neuroblasts1 and ovarian stem cells2,3 are well characterized models for stem cell biology. In both cell types, one daughter cell self-renews continuously while the other undergoes a limited number of divisions, stops to proliferate mitotically and differentiates. Whereas neuroblasts segregate the Trim–NHL (tripartite motif and Ncl-1, HT2A and Lin-41 domain)-containing protein Brain tumour (Brat) into one of the two daughter cells4,5,6, ovarian stem cells are regulated by an extracellular signal from the surrounding stem cell niche. After division, one daughter cell looses niche contact. It undergoes 4 transit-amplifying divisions to form a cyst of 16 interconnected cells that reduce their rate of growth and stop to proliferate mitotically. Here we show that the Trim–NHL protein Mei-P26 (refs 7, 8) restricts growth and proliferation in the ovarian stem cell lineage. Mei-P26 expression is low in stem cells but is strongly induced in 16-cell cysts. In mei-P26 mutants, transit-amplifying cells are larger and proliferate indefinitely leading to the formation of an ovarian tumour. Like brat, mei-P26 regulates nucleolar size and can induce differentiation in Drosophila neuroblasts, suggesting that these genes act through the same pathway. We identify Argonaute-1, a component of the RISC complex, as a common binding partner of Brat and Mei-P26, and show that Mei-P26 acts by inhibiting the microRNA pathway. Mei-P26 and Brat have a similar domain composition that is also found in other tumour suppressors and might be a defining property of a new family of microRNA regulators that act specifically in stem cell lineages.

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Figure 1: Differentiation and cell cycle defects in mei-P26 mutant ovaries.
Figure 2: Mei-P26 regulates cell and nucleolar size.
Figure 3: Bam requires the AGO1-binding protein Mei-P26 to induce proper cystocyte differentiation.
Figure 4: Mei-P26 regulates miRNAs.

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References

  1. Knoblich, J. A. Mechanisms of asymmetric stem cell division. Cell 132, 583–597 (2008)

    Article  CAS  Google Scholar 

  2. Fuller, M. T. & Spradling, A. C. Male and female Drosophila germline stem cells: two versions of immortality. Science 316, 402–404 (2007)

    Article  ADS  CAS  Google Scholar 

  3. Gilboa, L. & Lehmann, R. How different is Venus from Mars? The genetics of germ-line stem cells in Drosophila females and males. Development 131, 4895–4905 (2004)

    Article  CAS  Google Scholar 

  4. Lee, C. Y., Wilkinson, B. D., Siegrist, S. E., Wharton, R. P. & Doe, C. Q. Brat is a Miranda cargo protein that promotes neuronal differentiation and inhibits neuroblast self-renewal. Dev. Cell 10, 441–449 (2006)

    Article  CAS  Google Scholar 

  5. Bello, B., Reichert, H. & Hirth, F. The brain tumor gene negatively regulates neural progenitor cell proliferation in the larval central brain of Drosophila. Development 133, 2639–2648 (2006)

    Article  CAS  Google Scholar 

  6. Betschinger, J., Mechtler, K. & Knoblich, J. A. Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell 124, 1241–1253 (2006)

    Article  CAS  Google Scholar 

  7. Sekelsky, J. J. et al. Identification of novel Drosophila meiotic genes recovered in a P-element screen. Genetics 152, 529–542 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Page, S. L., McKim, K. S., Deneen, B., Van Hook, T. L. & Hawley, R. S. Genetic studies of mei-P26 reveal a link between the processes that control germ cell proliferation in both sexes and those that control meiotic exchange in Drosophila. Genetics 155, 1757–1772 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Reymond, A. et al. The tripartite motif family identifies cell compartments. EMBO J. 20, 2140–2151 (2001)

    Article  CAS  Google Scholar 

  10. Zaccai, M. & Lipshitz, H. D. Differential distributions of two adducin-like protein isoforms in the Drosophila ovary and early embryo. Zygote 4, 159–166 (1996)

    Article  CAS  Google Scholar 

  11. Lin, H., Yue, L. & Spradling, A. C. The Drosophila fusome, a germline-specific organelle, contains membrane skeletal proteins and functions in cyst formation. Development 120, 947–956 (1994)

    CAS  Google Scholar 

  12. Ohlmeyer, J. T. & Schupbach, T. Encore facilitates SCF-ubiquitin-proteasome-dependent proteolysis during Drosophila oogenesis. Development 130, 6339–6349 (2003)

    Article  CAS  Google Scholar 

  13. Chen, D. & McKearin, D. M. A discrete transcriptional silencer in the bam gene determines asymmetric division of the Drosophila germline stem cell. Development 130, 1159–1170 (2003)

    Article  CAS  Google Scholar 

  14. Lantz, V., Chang, J. S., Horabin, J. I., Bopp, D. & Schedl, P. The Drosophila orb RNA-binding protein is required for the formation of the egg chamber and establishment of polarity. Genes Dev. 8, 598–613 (1994)

    Article  CAS  Google Scholar 

  15. Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Frank, D. J., Edgar, B. A. & Roth, M. B. The Drosophila melanogaster gene brain tumor negatively regulates cell growth and ribosomal RNA synthesis. Development 129, 399–407 (2002)

    CAS  PubMed  Google Scholar 

  17. Grewal, S. S., Li, L., Orian, A., Eisenman, R. N. & Edgar, B. A. Myc-dependent regulation of ribosomal RNA synthesis during Drosophila development. Nature Cell Biol. 7, 295–302 (2005)

    Article  CAS  Google Scholar 

  18. Rudra, D. & Warner, J. R. What better measure than ribosome synthesis? Genes Dev. 18, 2431–2436 (2004)

    Article  CAS  Google Scholar 

  19. Tolia, N. H. & Joshua-Tor, L. Slicer and the argonautes. Nature Chem. Biol. 3, 36–43 (2007)

    Article  ADS  CAS  Google Scholar 

  20. Jin, Z. & Xie, T. Dcr-1 maintains Drosophila ovarian stem cells. Curr. Biol. 17, 539–544 (2007)

    Article  CAS  Google Scholar 

  21. Park, J. K., Liu, X., Strauss, T. J., McKearin, D. M. & Liu, Q. The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells. Curr. Biol. 17, 533–538 (2007)

    Article  CAS  Google Scholar 

  22. Brennecke, J., Hipfner, D. R., Stark, A., Russell, R. B. & Cohen, S. M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003)

    Article  CAS  Google Scholar 

  23. Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001)

    Article  ADS  CAS  Google Scholar 

  24. Clarke, M. F. & Fuller, M. Stem cells and cancer: two faces of eve. Cell 124, 1111–1115 (2006)

    Article  CAS  Google Scholar 

  25. Caussinus, E. & Gonzalez, C. Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nature Genet. 37, 1125–1129 (2005)

    Article  CAS  Google Scholar 

  26. Lee, C. Y. et al. Drosophila Aurora-A kinase inhibits neuroblast self-renewal by regulating aPKC/Numb cortical polarity and spindle orientation. Genes Dev. 20, 3464–3474 (2006)

    Article  CAS  Google Scholar 

  27. Wang, H. et al. Aurora-A acts as a tumor suppressor and regulates self-renewal of Drosophila neuroblasts. Genes Dev. 20, 3453–3463 (2006)

    Article  CAS  Google Scholar 

  28. Ross, D. T. et al. Systematic variation in gene expression patterns in human cancer cell lines. Nature Genet. 24, 227–235 (2000)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank V. Siegel, K. Mochizuki, G. B. Cebolla and S. Weitzer for comments on the manuscript, J. Stolte for assistance with quantitative PCRs, C. Richter and the other members of the Knoblich laboratory for discussion, B. Dickson, E. Izaurralde, P. Lasko, L. Luo, S. Hawley, D. McKearin, H. Richardson, F. Schnorrer, J. Skeath, D. Stein, L. Wong, the Bloomington Drosophila Stock Center, the Developmental Studies Hybridoma Bank (DSHB) and the Drosophila Genomics Resource Center (DGRC) for reagents, and M. Insco and M. Fuller for communicating results before publication. Work in the Knoblich laboratory is supported by the Austrian Academy of Sciences, the Wiener Wissenschafts-, Forschungs- und Technologiefonds (WWTF), the Austrian Science Fund (FWF) and the EU network ONCASYM; K.M. is supported by the Austrian Proteomics Platform (APP) of the Austrian Genome Program (GENAU).

Author Contributions J.A.K. and R.A.N. designed the study. R.A.N. performed the oogenesis experiments. J.B. and K.M. contributed biochemical data (Fig. 3h and Supplementary Fig. 4a, b). A.F. contributed the S2 luciferase assay (Supplementary Fig. 7c, d). I.P. assisted in the experiment in Fig. 3f, g and performed experiments in the larval brain (Supplementary Fig. 3). S.C. and N.B. designed the microRNA quantitative PCR experiment, which was performed by N.B. (Fig. 4a and Supplementary Fig. 7a, b). J.A.K. wrote the paper.

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Author notes

  1. Joerg Betschinger & Stephen M. Cohen

    Present address: Present addresses: Wellcome Trust Centre for Stem Cell Research (CSCR), University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK (J.B.); Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, 117604, Singapore (S.M.C.).,

Authors and Affiliations

  1. Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Dr Bohr Gasse 3, 1030 Vienna, Austria,

    Ralph A. Neumüller, Joerg Betschinger, Anja Fischer, Ingrid Poernbacher, Karl Mechtler & Juergen A. Knoblich

  2. European Molecular Biology Laboratory (EMBL), Meyerhofstraße 1, 69117 Heidelberg, Germany,

    Natascha Bushati & Stephen M. Cohen

  3. Research Institute of Molecular Pathology (IMP), Dr Bohr-Gasse 7, 1030 Vienna, Austria,

    Karl Mechtler

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Correspondence to Juergen A. Knoblich.

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Neumüller, R., Betschinger, J., Fischer, A. et al. Mei-P26 regulates microRNAs and cell growth in the Drosophila ovarian stem cell lineage. Nature 454, 241–245 (2008). https://doi.org/10.1038/nature07014

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