A nuclear role for the Argonaute protein AGO2 in mammalian gametogenesis

Abstract

Argonaute 2 (AGO2) is a ubiquitously expressed protein critical for regulation of mRNA translation and vital to animal development. AGO2 protein is found in both cytoplasmic and nuclear compartments, and while its cytoplasmic role is well studied, the biological relevance of nuclear AGO2 is unclear. Here, we address this problem in vivo, using developing spermatogenic cells as a model. Remarkably, we find that AGO2 acts in the germ cell nucleus to positively regulate protein expression. We show that AGO2 dynamically binds both chromatin and nuclear mRNA transcripts of hundreds of genes required for sperm production, and germline conditional knockout (cKO) of Ago2 causes depletion of the corresponding proteins, along with defects in sperm number and morphology. Nuclear AGO2 partners with splicing, export, and chromatin factors to promote transcript export and protein expression. Together, our data reveal an unexpected role for nuclear AGO2 in enhancing expression of developmentally important genes.