An mTORC1-dependent switch orchestrates the transition between mouse spermatogonial stem cells and clones of progenitor spermatogonia

Shinnosuke Suzuki, John R. McCarrey, Brian P. Hermann

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Spermatogonial stem cells (SSCs) sustain spermatogenesis by balancing self-renewal and initiation of differentiation to produce progenitor spermatogonia committed to forming sperm. To define the regulatory logic among SSCs and progenitors, we performed single-cell RNA velocity analyses and validated results in vivo. A predominant quiescent SSC population spawns a small subset of cell-cycle-activated SSCs via mitogen-activated protein kinase (MAPK)/AKT signaling. Activated SSCs form early progenitors and mTORC1 inhibition drives activated SSC accumulation consistent with blockade to progenitor formation. Mechanistically, mTORC1 inhibition suppresses transcription among spermatogonia and specifically alters expression of insulin growth factor (IGF) signaling in early progenitors. Tex14−/− testes lacking intercellular bridges do not accumulate activated SSCs following mTORC1 inhibition, indicating that steady-state mTORC1 signaling drives activated SSCs to produce progenitor clones. These results are consistent with a model of SSC self-renewal dependent on interconversion between activated and quiescent SSCs, and mTORC1-dependent initiation of differentiation from SSCs to progenitor clones. Suzuki et al. define relationships between subsets of adult mouse SSCs and progenitor spermatogonia using single-cell RNA velocity analyses and in vivo validations. Quiescent SCCs convert to cell-cycle-activated SCCs via MAPK/AKT signaling. Activated SCCs are driven to become early progenitor clones ready to initiate differentiation through mTORC1 signaling.

Original languageEnglish (US)
Article number108752
JournalCell Reports
Volume34
Issue number7
DOIs
StatePublished - Feb 16 2021
Externally publishedYes

Keywords

  • cell fate
  • RNA velocity
  • single cell
  • spermatogenesis
  • subpopulations
  • testis
  • undifferentiated spermatogonia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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