SummaryIn mouse, although four Argonaute (AGO) proteins with partly overlapping functions in small-RNA pathways exist, only Ago2 deficiency causes embryonic lethality. To investigate the role of AGO2 during mouse early development, we generated Ago2-deficient mouse embryonic stem cells (mESCs) and performed a detailed characterization of their differentiation potential. Ago2 disruption caused a global reduction of microRNAs, which resulted in the misregulation of only a limited number of transcripts. We demonstrated, both in vivo and in vitro, that AGO2 is dispensable for the embryonic germ-layer formation. However, Ago2-deficient mESCs showed a specific defect during conversion into extra-embryonic endoderm cells. We proved that this defect is cell autonomous and can be rescued by both a catalytically active and an inactive Ago2, but not by Ago2 deprived of its RNA binding capacity or by Ago1 overexpression. Overall, our results suggest a role for AGO2 in stem cell differentiation.
A gene regulation network orchestrates processes ensuring the maintenance of cellular identity and genome integrity. Small
RNA
s generated by the
RNA
se
III DICER
have emerged as central players in this network. Moreover, deletion of
Dicer
in mice leads to early embryonic lethality. To better understand the underlying mechanisms leading to this phenotype, we generated
Dicer
‐deficient mouse embryonic stem cells (
mESC
s). Their detailed characterization revealed an impaired differentiation potential, and incapacity to exit from the pluripotency state. We also observed a strong accumulation of
LINE
‐1 (L1s) transcripts, which was translated at protein level and led to an increased L1s retrotransposition. Our findings reveal
Dicer
as a new essential player that sustains
mESC
s self‐renewal and genome integrity by controlling L1s regulation.
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