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USP7 controls NGN3 stability and pancreatic endocrine lineage development

Author

Listed:
  • Teodora Manea

    (King’s College London)

  • Jessica Kristine Nelson

    (The Francis Crick Institute
    Institute of Cancer Research)

  • Cristina Maria Garrone

    (King’s College London)

  • Karin Hansson

    (Institute of Cancer Research)

  • Ian Evans

    (The Francis Crick Institute
    Institute of Cancer Research)

  • Axel Behrens

    (The Francis Crick Institute
    Institute of Cancer Research
    Imperial College
    Imperial College)

  • Rocio Sancho

    (King’s College London
    University Hospital Carl Gustav Carus at the Technische Universität Dresden)

Abstract

Understanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited.

Suggested Citation

  • Teodora Manea & Jessica Kristine Nelson & Cristina Maria Garrone & Karin Hansson & Ian Evans & Axel Behrens & Rocio Sancho, 2023. "USP7 controls NGN3 stability and pancreatic endocrine lineage development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38146-9
    DOI: 10.1038/s41467-023-38146-9
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    References listed on IDEAS

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    1. Lorna Kategaya & Paola Di Lello & Lionel Rougé & Richard Pastor & Kevin R. Clark & Jason Drummond & Tracy Kleinheinz & Eva Lin & John-Paul Upton & Sumit Prakash & Johanna Heideker & Mark McCleland & M, 2017. "USP7 small-molecule inhibitors interfere with ubiquitin binding," Nature, Nature, vol. 550(7677), pages 534-538, October.
    2. Åsa Apelqvist & Hao Li & Lukas Sommer & Paul Beatus & David J. Anderson & Tasuku Honjo & Martin Hrabě de Angelis & Urban Lendahl & Helena Edlund, 1999. "Notch signalling controls pancreatic cell differentiation," Nature, Nature, vol. 400(6747), pages 877-881, August.
    3. Marissa A. Scavuzzo & Matthew C. Hill & Jolanta Chmielowiec & Diane Yang & Jessica Teaw & Kuanwei Sheng & Yuelin Kong & Maria Bettini & Chenghang Zong & James F. Martin & Malgorzata Borowiak, 2018. "Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis," Nature Communications, Nature, vol. 9(1), pages 1-21, December.
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