Asymmetric division of adult stem cells generates one self-renewing stem cell and one differentiating cell, thereby maintaining tissue homeostasis. A decline in stem cell function has been proposed to contribute to tissue ageing, although the underlying mechanism is poorly understood. Here we show that changes in the stem cell orientation with respect to the niche during ageing contribute to the decline in spermatogenesis in the male germ line of Drosophila. Throughout the cell cycle, centrosomes in germline stem cells (GSCs) are oriented within their niche and this ensures asymmetric division. We found that GSCs containing misoriented centrosomes accumulate with age and that these GSCs are arrested or delayed in the cell cycle. The cell cycle arrest is transient, and GSCs appear to re-enter the cell cycle on correction of centrosome orientation. On the basis of these findings, we propose that cell cycle arrest associated with centrosome misorientation functions as a mechanism to ensure asymmetric stem cell division, and that the inability of stem cells to maintain correct orientation during ageing contributes to the decline in spermatogenesis. We also show that some of the misoriented GSCs probably originate from dedifferentiation of spermatogonia.
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Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006)
Spradling, A., Drummond-Barbosa, D. & Kai, T. Stem cells find their niche. Nature 414, 98–104 (2001)
Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)
Yamashita, Y. M., Fuller, M. T. & Jones, D. L. Signaling in stem cell niches: lessons from the Drosophila germline. J. Cell Sci. 118, 665–672 (2005)
Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006)
Sharpless, N. E. & Depinho, R. A. How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007)
Serrano, M. & Blasco, M. A. Cancer and ageing: convergent and divergent mechanisms. Nature Rev. Mol. Cell Biol. 8, 715–722 (2007)
Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005)
Krishnamurthy, J. et al. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443, 453–457 (2006)
Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006)
Janzen, V. et al. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a . Nature 443, 421–426 (2006)
Tulina, N. & Matunis, E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 294, 2546–2549 (2001)
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)
Yamashita, Y. M., Jones, D. L. & Fuller, M. T. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301, 1547–1550 (2003)
Yamashita, Y. M., Mahowald, A. P., Perlin, J. R. & Fuller, M. T. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315, 518–521 (2007)
Rusan, N. M. & Peifer, M. A role for a novel centrosome cycle in asymmetric cell division. J. Cell Biol. 177, 13–20 (2007)
Rebollo, E. et al. Functionally unequal centrosomes drive spindle orientation in asymmetrically dividing Drosophila neural stem cells. Dev. Cell 12, 467–474 (2007)
Boyle, M., Wong, C., Rocha, M. & Jones, D. L. Decline in self-renewal factors contributes to aging of the stem cell niche in the Drosophila testis. Cell Stem Cell 1, 470–478 (2007)
Brawley, C. & Matunis, E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo . Science 304, 1331–1334 (2004)
Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004)
Schulz, C. et al. A misexpression screen reveals effects of bag-of-marbles and TGFβ class signaling on the Drosophila male germ-line stem cell lineage. Genetics 167, 707–723 (2004)
Kaltschmidt, J. A., Davidson, C. M., Brown, N. H. & Brand, A. H. Rotation and asymmetry of the mitotic spindle direct asymmetric cell division in the developing central nervous system. Nature Cell Biol. 2, 7–12 (2000)
Wallenfang, M. R., Nayak, R. & DiNardo, S. Dynamics of the male germline stem cell population during aging of Drosophila melanogaster . Aging Cell 5, 297–304 (2006)
Patel, N. H., Snow, P. M. & Goodman, C. S. Characterization and cloning of fasciclin III: a glycoprotein expressed on a subset of neurons and axon pathways in Drosophila . Cell 48, 975–988 (1987)
Ding, D., Parkhurst, S. M. & Lipshitz, H. D. Different genetic requirements for anterior RNA localization revealed by the distribution of Adducin-like transcripts during Drosophila oogenesis. Proc. Natl Acad. Sci. USA 90, 2512–2516 (1993)
Gonczy, P. & DiNardo, S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis. Development 122, 2437–2447 (1996)
Fuller, M. T. Spermatogenesis. In The Development of Drosophila melanogaster (eds Bate, M. & Martinez-Arias, A.) 71–147 (Cold Spring Harbor Laboratory Press, 1993)
We thank C. Gonzalez, D. McKearin, N. Rusan, M. Peifer and the Bloomington Stock Center for fly stocks; R. Lehmann, C. Field and the Developmental Studies Hybridoma Bank for antibodies; M. Kiel and D. Nakada for help with X-ray irradiation; and S. Morrison and T. Mahowald for comments on the manuscript. This research was supported by a University of Michigan start-up fund, March of Dimes Basil O’Conner Starter Scholar Research Award and the Searle Scholar Program (to Y.M.Y.), and NIH grants P01 DK53074 (to M.T.F.) and R01GM072006 (to A.J.H.).
Author Contributions Y.M.Y. designed research. J.C. and A.J.H. designed and conducted time-lapse imaging of centrosome behaviour. J.C., N.T., N.H. and Y.M.Y. performed other experiments. M.T.F. contributed to research design for Figs 1 and 2. Y.M.Y. wrote the manuscript.
This file contains Supplementary Figures S1-S3 with Legends, Supplementary Table 1 and Supplementary Movies 1 Legend. (PDF 1755 kb)
This file contains Supplementary Movie S1 showing time-lapse live imaging of centrosome behavior in a misoriented GSC. (AVI 55853 kb)
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Cheng, J., Türkel, N., Hemati, N. et al. Centrosome misorientation reduces stem cell division during ageing. Nature 456, 599–604 (2008). https://doi.org/10.1038/nature07386
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