Essential and overlapping functions for mammalian argonautes in microRNA silencing

Hong Su, Melanie I. Trombly, Jian Chen, Xiaozhong Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

MicroRNA (miRNA) silencing fine-tunes protein output and regulates diverse biological processes. Argonaute (Ago) proteins are the core effectors of the miRNA pathway. In lower organisms, multiple Agos have evolved specialized functions for distinct RNA silencing pathways. However, the roles of mammalian Agos have not been well characterized. Here we show that mouse embryonic stem (ES) cells deficient for Agol-4 are completely defective in miRNA silencing and undergo apoptosis. In miRNA silencing-defective ES cells, the proapoptotic protein Bim, a miRNA target, is increased, and up-regulation of Bim is sufficient to induce ES cell apoptosis. Expression of activated Akt inhibits Bim expression and partially rescues the growth defect in Ago-deficient ES cells. Furthermore, reintroduction of any single Ago into Ago-deficient cells is able to rescue the endogenous miRNA silencing defect and apoptosis. Consistent with this, each Ago is functionally equivalent with bulged miRNA duplexes for translational repression, whereas Ago1 and Ago2 appear to be more effective at utilizing perfectly matched siRNAs. Thus, our results demonstrate that mammalian Agos all contribute to miRNA silencing, and individual Agos have largely overlapping functions in this process.

Original languageEnglish (US)
Pages (from-to)304-317
Number of pages14
JournalGenes and Development
Volume23
Issue number3
DOIs
StatePublished - Feb 1 2009

Keywords

  • Apoptosis
  • Argonaute
  • MicroRNA
  • SiRNA
  • Stem cells

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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