The let-7-Imp axis regulates aging of the Drosophila testis stem cell niche.

Adult stem cells support tissue homeostasis and repair throughout the life of an individual. However, numerous intrinsic and extrinsic changes occur with age that result in altered stem cell behavior and reduced tissue maintenance and regeneration. In the Drosophila testis, stem cells surround and contact the apical hub, a cluster of somatic cells that express the self-renewal factor Unpaired (Upd), which activates the JAK-STAT pathway in adjacent stem cells. However, aging results in a dramatic decrease in upd expression, with a concomitant loss of germline stem cells (GSCs). Here we present genetic and biochemical data to demonstrate that IGF-II mRNA binding protein (Imp) counteracts endogenous small interfering RNAs to stabilize upd RNA and contribute to maintenance of the niche. However, Imp expression decreases in hub cells of older males, similar to upd, which is due to targeting of Imp by the heterochronic microRNA let-7. Therefore, in the absence of Imp, upd mRNA becomes unprotected and susceptible to degradation. Understanding the mechanistic basis for aging-related changes in stem cell behavior will lead to the development of strategies to treat age-onset diseases and facilitate stem cell based therapies in older individuals. Overall design: Examination of small RNA levels in testes from young (1day old) and aged (30days old) males of Drosophila melanogaster by deep sequencing (using Illumina GAII).

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Toledano H, D'Alterio C, Czech B, Levine E, Jones DL