Abstract
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.
Highlights
Ageing leads to reduced tissue homeostasis and a decline in the ability to replace damaged cells by new functional ones[1]
In the Drosophila melanogaster (Drosophila) testis, mature sperm cells are generated by germline stem cells (GSCs) that are located at the apical tip of the testis
Statistical significance was determined by one-way ANOVA and post hoc analysis was performed with Tukey multi-comparison test. **P ≤ 0.005 between 15 and 1-day and between 30 and 1-day. e–g’ Testes of control green fluorescent protein (GFP) sensor (e, e’) and miR-9a sensor 1-day (f, f’) and 30-days (g, g’) stained for Fas[3] to mark the hub, Vasa to mark the germ cells and GFP
Summary
Ageing leads to reduced tissue homeostasis and a decline in the ability to replace damaged cells by new functional ones[1]. In the Drosophila melanogaster (Drosophila) testis, mature sperm cells are generated by germline stem cells (GSCs) that are located at the apical tip of the testis These cells, together with Cyst stem cells (CySCs) co-habitat in the niche and adhere around a cluster of somatic cells called the hub[3,4,5]. B Testes from 1-day, 15-days, or 30-days-old males (green, mature sperms; ImpCB04573) immunostained for Vasa (red, germ cells) and Fas[3] (blue, hub and seminal vesicles). E–g’ Testes of control GFP sensor (e, e’) and miR-9a sensor 1-day (f, f’) and 30-days (g, g’) stained for Fas[3] (blue) to mark the hub (asterisks), Vasa to mark the germ cells (red) and GFP (green). A control sensor is expressed in all cells at the apical tip of the testis including: hub, GSCs, CySCs, cyst cells (arrowhead), spermatogonia and spermatocytes. MiR9a directly downregulates Neural-Cadherin (N-cad) to control the adhesion between GSCs and the hub, promoting GSCs detachment from the niche to allow differentiation and functional spermatogenesis
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