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Tracing the transitions from pluripotency to germ cell fate with CRISPR screening

Author

Listed:
  • Jamie A. Hackett

    (University of Cambridge
    European Molecular Biology Laboratory (EMBL)
    University of Cambridge)

  • Yun Huang

    (University of Cambridge
    University of Cambridge)

  • Ufuk Günesdogan

    (University of Cambridge
    University of Cambridge
    Göttingen Center for Molecular Biosciences)

  • Kristjan A. Gretarsson

    (European Molecular Biology Laboratory (EMBL))

  • Toshihiro Kobayashi

    (University of Cambridge
    University of Cambridge
    National Institute for Physiological Sciences)

  • M. Azim Surani

    (University of Cambridge
    University of Cambridge)

Abstract

Early mammalian development entails transit through naive pluripotency towards post-implantation epiblast, which subsequently gives rise to primordial germ cells (PGC), the founding germline population. To investigate these cell fate transitions, we developed a compound-reporter to track cellular identity in a model of PGC specification (PGC-like cells; PGCLC), and coupled it with genome-wide CRISPR screening. We identify key genes both for exit from pluripotency and for acquisition of PGC fate, and characterise a central role for the transcription regulators Nr5a2 and Zfp296 in germline ontogeny. Abrogation of these genes results in widespread activation (Nr5a2−/−) or inhibition (Zfp296−/−) of WNT pathway factors in PGCLC. This leads to aberrant upregulation of the somatic programme or failure to activate germline genes, respectively, and consequently loss of germ cell identity. Our study places Zfp296 and Nr5a2 as key components of an expanded PGC gene regulatory network, and outlines a transferable strategy for identifying critical regulators of complex cell fate decisions.

Suggested Citation

  • Jamie A. Hackett & Yun Huang & Ufuk Günesdogan & Kristjan A. Gretarsson & Toshihiro Kobayashi & M. Azim Surani, 2018. "Tracing the transitions from pluripotency to germ cell fate with CRISPR screening," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06230-0
    DOI: 10.1038/s41467-018-06230-0
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