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The let-7–Imp axis regulates ageing of the Drosophila testis stem-cell niche

Abstract

Adult stem cells support tissue homeostasis and repair throughout the life of an individual. During ageing, numerous intrinsic and extrinsic changes occur that result in altered stem-cell behaviour and reduced tissue maintenance and regeneration. In the Drosophila testis, ageing results in a marked decrease in the self-renewal factor Unpaired (Upd), leading to a concomitant loss of germline stem cells. Here we demonstrate that IGF-II messenger RNA binding protein (Imp) counteracts endogenous small interfering RNAs to stabilize upd (also known as os) RNA. However, similar to upd, Imp expression decreases in the hub cells of older males, which is due to the targeting of Imp by the heterochronic microRNA let-7. In the absence of Imp, upd mRNA therefore becomes unprotected and susceptible to degradation. Understanding the mechanistic basis for ageing-related changes in stem-cell behaviour will lead to the development of strategies to treat age-onset diseases and facilitate stem-cell-based therapies in older individuals.

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Figure 1: Imp regulates upd levels and GSC maintenance in the testis.
Figure 2: Imp binds to upd mRNA and counteracts siRNA-mediated degradation.
Figure 3: Imp counteracts AGO2 and Dicer-2 to regulate upd levels and stem-cell maintenance.
Figure 4: Imp is targeted by let-7 miRNA in the testis.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The small RNA libraries from the testes of 1-day-old and 30-day-old flies have been deposited in the Gene Expression Omnibus database under accession GSE37041.

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Acknowledgements

We are grateful to D. St Johnston, W. Chia, P. Macdonald, R. Carthew, E. Bach, D. Harrison, T. Volk, U. Heberlein, A. Spradling, J. Kadonaga, G. Hannon, T. Hays, N. Sokol, H. Siomi and P. Lasko for reagents and fly stocks, to C. Doe, R. Hans, G. Volohonsky, T. Juven-Gershon, A. Pasquinelli, R. Zhou and S. Aigner for guidance on methods used in this manuscript, to O. Tam for computational support, and to C. Koehler for technical assistance. This work was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, the Ellison Medical Foundation, the Emerald Foundation, the American Federation for Aging Research, and the National Institutes of Health (to D.L.J.). B.C. is supported by a PhD fellowship from the Boehringer Ingelheim Fonds. E.L. is supported by the National Science Foundation.

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H.T., C.D. and D.L.J. designed experiments. H.T. and C.D. performed experiments. B.C. generated and analysed small RNA libraries. E.L. performed bioinformatic analysis to identify Imp-binding sequences. H.T., C.D., B.C. and D.L.J. evaluated the data and wrote the manuscript.

Corresponding author

Correspondence to D. Leanne Jones.

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The authors declare no competing financial interests.

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Toledano, H., D’Alterio, C., Czech, B. et al. The let-7–Imp axis regulates ageing of the Drosophila testis stem-cell niche. Nature 485, 605–610 (2012). https://doi.org/10.1038/nature11061

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