RNA Binding Protein Nanos2 Organizes Post-transcriptional Buffering System to Retain Primitive State of Mouse Spermatogonial Stem Cells

In many adult tissues, homeostasis relies on self-renewing stem cells that are primed for differentiation. The reconciliation mechanisms of these characteristics remain a fundamental question in stem cell biology. We propose that regulation at the post-transcriptional level is essential for homeostasis in murine spermatogonial stem cells (SSCs). Here, we show that Nanos2, an evolutionarily conserved RNA-binding protein, works with other cellular messenger ribonucleoprotein (mRNP) components to ensure the primitive status of SSCs through a dual mechanism that involves (1) direct recruitment and translational repression of genes that promote spermatogonial differentiation and (2) repression of the target of rapamycin complex 1 (mTORC1), a well-known negative pathway for SSC self-renewal, by sequestration of the core factor mTOR in mRNPs. This mechanism links mRNA turnover to mTORC1 signaling through Nanos2-containing mRNPs and establishes a post-transcriptional buffering system to facilitate SSC homeostasis in the fluctuating environment within the seminiferous tubule. [Display omitted] •Cytoplasmic mRNP formation is critical for spermatogonial stem cell (SSC) maintenance•Nanos2 promotes condensation of cytoplasmic mRNPs•Nanos2/mRNPs repress mTORC1 activity by trapping mTOR in cytoplasmic mRNPs•Nanos2-resistant Sohlh2 is sufficient to trigger the differentiation of SSCs Spermatogonial stem cells (SSCs) can self-renew, contributing to continuous spermatozoa production. Zhou et al. implicate Nanos2 in the repression of murine spermatogonia differentiation. Nanos2 mediates direct translational repression of differentiation-related transcripts and inhibits mTORC1 signaling by sequestrating mTOR protein in mRNPs, thereby providing a buffering system to facilitate SSC homeostasis.