Ageing is characterized by a decline in stem cell functionality leading to dampened tissue regeneration. While the expression of microRNAs across multiple species is markedly altered with age, the mechanism by which they govern stem cell-sustained tissue regeneration is unknown. We report that in the Drosophila testis, the conserved miR-9a is expressed in germline stem cells and its levels are significantly elevated during ageing. Transcriptome and functional analyses show that miR-9a directly regulates the expression of the adhesion molecule N-cadherin (N-cad). miR-9a null mutants maintain a higher number of stem cells even in the aged tissue. Remarkably, this rise fails to improve tissue regeneration and results in reduced male fertility. Similarly, overexpression of N-cad also results in elevated stem cell number and decreased regeneration. We propose that miR-9a downregulates N-cad to enable adequate detachment of stem cells toward differentiation, thus providing the necessary directionality toward terminal differentiation and spermatogenesis.
Bibliographical noteFunding Information:
We are grateful to F.B. Gao, E.C. Lai, S.M. Cohen, S.F. Önel, T. Uemura, D. Ideses, T. Juven-Gershon, H.J. Bellen, O. Schuldiner, N. Issman, K. Yacobi-Sharon, and the Developmental Studies Hybridoma Bank for gracious gifts of Drosophila stocks, plasmids, and antibodies that were critical for this study. We thank N. Sher and the Bioinformatics unit of University of Haifa for transcriptome analysis. We also thank L. Barki-Harrington, D. Ideses, and H. Kaspi for advices and comments. This work was supported by the Israel Science Foundation (ISF) personal grant (1510/14), the Binational Science Foundation (BSF)-USA-Israel (2015398) and by Victoria and Marvin Sadowski Fund (Canada).
© 2017 The Author(s).
ASJC Scopus subject areas
- Chemistry (all)
- Biochemistry, Genetics and Molecular Biology (all)
- Physics and Astronomy (all)