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Stem cell division is regulated by the microRNA pathway

Abstract

One of the key characteristics of stem cells is their capacity to divide for long periods of time in an environment where most of the cells are quiescent. Therefore, a critical question in stem cell biology is how stem cells escape cell division stop signals. Here, we report the necessity of the microRNA (miRNA) pathway1,2,3,4 for proper control of germline stem cell (GSC) division in Drosophila melanogaster. Analysis of GSCs mutant for dicer-1 (dcr-1), the double-stranded RNaseIII essential for miRNA biogenesis, revealed a marked reduction in the rate of germline cyst production. These dcr-1 mutant GSCs exhibit normal identity but are defective in cell cycle control. On the basis of cell cycle markers and genetic interactions, we conclude that dcr-1 mutant GSCs are delayed in the G1 to S transition, which is dependent on the cyclin-dependent kinase inhibitor Dacapo, suggesting that miRNAs are required for stem cells to bypass the normal G1/S checkpoint. Hence, the miRNA pathway might be part of a mechanism that makes stem cells insensitive to environmental signals that normally stop the cell cycle at the G1/S transition.

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Figure 1: Loss of Dcr-1 function in GSCs reduces the rate of egg chamber production.
Figure 2: dcr-1 mutant GSCs remain in the stem cell niche and retain stem cell identity.
Figure 3: dcr-1 causes a cell cycle delay in GSCs.
Figure 4: The GSC division defect is dependent on Dap.

References

  1. He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nature Rev. Genet. 5, 522–531 (2004)

    CAS  Article  Google Scholar 

  2. Nakahara, K. & Carthew, R. W. Expanding roles for miRNAs and siRNAs in cell regulation. Curr. Opin. Cell Biol. 16, 127–133 (2004)

    CAS  Article  Google Scholar 

  3. Bartel, B. & Bartel, D. P. MicroRNAs: at the root of plant development? Plant Physiol. 132, 709–717 (2003)

    ADS  CAS  Article  Google Scholar 

  4. Ambros, V. microRNAs: tiny regulators with great potential. Cell 107, 823–826 (2001)

    CAS  Article  Google Scholar 

  5. Bernstein, E. et al. Dicer is essential for mouse development. Nature Genet. 35, 215–217 (2003)

    CAS  Article  Google Scholar 

  6. Schauer, S. E., Jacobsen, S. E., Meinke, D. W. & Ray, A. DICER-LIKE1: blind men and elephants in Arabidopsis development. Trends Plant Sci. 7, 487–491 (2002)

    CAS  Article  Google Scholar 

  7. Carmell, M. A., Xuan, Z., Zhang, M. Q. & Hannon, G. J. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 16, 2733–2742 (2002)

    CAS  Article  Google Scholar 

  8. Suh, M. R. et al. Human embryonic stem cells express a unique set of microRNAs. Dev. Biol. 270, 488–498 (2004)

    CAS  Article  Google Scholar 

  9. Houbaviy, H. B., Murray, M. F. & Sharp, P. A. Embryonic stem cell-specific MicroRNAs. Dev. Cell 5, 351–358 (2003)

    CAS  Article  Google Scholar 

  10. Lee, Y. S. et al. Distinct roles for Drosophila Dicer-1 and Dicer-2 in the siRNA/miRNA silencing pathways. Cell 117, 69–81 (2004)

    CAS  Article  Google Scholar 

  11. Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001)

    ADS  CAS  Article  Google Scholar 

  12. 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)

    CAS  Article  Google Scholar 

  13. Johnson, J., Canning, J., Kaneko, T., Pru, J. K. & Tilly, J. L. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 428, 145–150 (2004)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  15. Newfeld, S. J. et al. Mothers against dpp participates in a DDP/TGF-β responsive serine-threonine kinase signal transduction cascade. Development 124, 3167–3176 (1997)

    CAS  Google Scholar 

  16. Song, X. et al. Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development 131, 1353–1364 (2004)

    CAS  Article  Google Scholar 

  17. Shcherbata, H. R., Althauser, C., Findley, S. D. & Ruohola-Baker, H. The mitotic-to-endocycle switch in Drosophila follicle cells is executed by Notch-dependent regulation of G1/S, G2/M and M/G1 cell-cycle transitions. Development 131, 3169–3181 (2004)

    CAS  Article  Google Scholar 

  18. Calvi, B. R. & Lilly, M. A. Fluorescent BrdU labeling and nuclear flow sorting of the Drosophila ovary. Methods Mol. Biol. 247, 203–213 (2004)

    CAS  Google Scholar 

  19. Gonczy, P. & DiNardo, S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis. Development 122, 2437–2447 (1996)

    CAS  Google Scholar 

  20. Kiger, A. A., Jones, D. L., Schulz, C., Rogers, M. B. & Fuller, M. T. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 294, 2542–2545 (2001)

    ADS  CAS  Article  Google Scholar 

  21. de Nooij, J. C., Letendre, M. A. & Hariharan, I. K. A cyclin-dependent kinase inhibitor, Dacapo, is necessary for timely exit from the cell cycle during Drosophila embryogenesis. Cell 87, 1237–1247 (1996)

    CAS  Article  Google Scholar 

  22. Pavletich, N. P. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol. 287, 821–828 (1999)

    CAS  Article  Google Scholar 

  23. Meyer, C. A. et al. Drosophila p27Dacapo expression during embryogenesis is controlled by a complex regulatory region independent of cell cycle progression. Development 129, 319–328 (2002)

    CAS  Google Scholar 

  24. Datto, M. B. et al. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc. Natl Acad. Sci. USA 92, 5545–5549 (1995)

    ADS  CAS  Article  Google Scholar 

  25. Lane, M. E. et al. Dacapo, a cyclin-dependent kinase inhibitor, stops cell proliferation during Drosophila development. Cell 87, 1225–1235 (1996)

    CAS  Article  Google Scholar 

  26. Enright, A. J. et al. MicroRNA targets in Drosophila . Genome Biol. 5, R1 (2003)

    Article  Google Scholar 

  27. Stark, A., Brennecke, J., Russell, R. B. & Cohen, S. M. Identification of Drosophila MicroRNA targets. PLoS Biol. 1, E60 (2003)

    Article  Google Scholar 

  28. Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003)

    CAS  Article  Google Scholar 

  29. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature doi:10.1038/nature03552 (in the press)

  30. Margolis, J. & Spradling, A. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 121, 3797–3807 (1995)

    CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Calvi, B. Wakimoto and E. Ward for comments on the manuscript, and the members of the H.R.-B. laboratory for suggestions throughout the course of this study. We also thank E. Kerr for making dacapo constructs; V. Shcherbatyy for creating transgenic lines; B. Akiyashi for UAS-Dap experiments; K. Kim for the dcr-1d102 strain; and M. Lilly, C. Lehner, I. Hariharan, T. Orr-Weaver, D. McKearin, P. ten Dijke, A. Spradling and C.-H. Heldin for flies, antibodies and advice. This work was supported by the Schultz Fellowship for S.D.H., grants from the National Institutes of Health to R.W.C and H. R.-B., and the American Heart Association and the American Cancer Society to H.R.-B.

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Correspondence to H. Ruohola-Baker.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods, additional references, Supplementary Table S1 and Supplementary Figure Legends. (DOC 50 kb)

Supplementary Figure S1

The dcr-1d102 allele yields a phenotype identical to, albeit slightly milder than the dcr-1Q1147X allele. (JPG 309 kb)

Supplementary Figure S2

The dcr1-related reduction in cell division rate and cell cycle delay are germline stem cell-specific. (a-a'') (JPG 455 kb)

Supplementary Figure S3

Analysis of Dacapo expression in GSCs. (JPG 459 kb)

Supplementary Figure S4

Computational prediction of miRNA binding sites in the dap 3' UTR. (DOC 29 kb)

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Hatfield, S., Shcherbata, H., Fischer, K. et al. Stem cell division is regulated by the microRNA pathway. Nature 435, 974–978 (2005). https://doi.org/10.1038/nature03816

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