Piwi reduction in the aged niche eliminates germline stem cells via Toll-GSK3 signaling

Nat Commun. 2020 Jun 19;11(1):3147. doi: 10.1038/s41467-020-16858-6.

Abstract

Transposons are known to participate in tissue aging, but their effects on aged stem cells remain unclear. Here, we report that in the Drosophila ovarian germline stem cell (GSC) niche, aging-related reductions in expression of Piwi (a transposon silencer) derepress retrotransposons and cause GSC loss. Suppression of Piwi expression in the young niche mimics the aged niche, causing retrotransposon depression and coincident activation of Toll-mediated signaling, which promotes Glycogen synthase kinase 3 activity to degrade β-catenin. Disruption of β-catenin-E-cadherin-mediated GSC anchorage then results in GSC loss. Knocking down gypsy (a highly active retrotransposon) or toll, or inhibiting reverse transcription in the piwi-deficient niche, suppresses GSK3 activity and β-catenin degradation, restoring GSC-niche attachment. This retrotransposon-mediated impairment of aged stem cell maintenance may have relevance in many tissues, and could represent a viable therapeutic target for aging-related tissue degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Argonaute Proteins / genetics
  • Argonaute Proteins / metabolism*
  • Cadherins / metabolism
  • Cellular Senescence*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster* / genetics
  • Drosophila melanogaster* / metabolism
  • Female
  • Gene Silencing
  • Germ Cells / metabolism*
  • Glycogen Synthase Kinase 3 / metabolism
  • Ovary / cytology
  • Ovary / metabolism
  • Retroelements / genetics
  • Signal Transduction
  • Stem Cell Niche / physiology
  • Stem Cells / metabolism
  • Toll-Like Receptors / metabolism
  • beta Catenin / metabolism

Substances

  • Argonaute Proteins
  • Cadherins
  • Drosophila Proteins
  • Retroelements
  • Toll-Like Receptors
  • beta Catenin
  • piwi protein, Drosophila
  • Glycogen Synthase Kinase 3