Centrosome misorientation reduces stem cell division during ageing

Abstract

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.

Figure 1: Drosophila testis undergoes an age-related decline in spermatogenesis.
Figure 2: Misoriented GSCs increase with age.
Figure 3: Misoriented GSCs divide less frequently compared with oriented GSCs.
Figure 4: Misoriented GSCs correct centrosome orientation before mitosis.
Figure 5: Dedifferentiated GSCs have a higher frequency of centrosome misorientation.
Figure 6: Evidence that LacZ + GSCs are generated by dedifferentiation

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Acknowledgements

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.

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Correspondence to Yukiko M. Yamashita.

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Supplementary Information

This file contains Supplementary Figures S1-S3 with Legends, Supplementary Table 1 and Supplementary Movies 1 Legend. (PDF 1755 kb)

Supplementary Movie S1

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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