USP7 controls NGN3 stability and pancreatic endocrine lineage development

Teodora Manea, Jessica Kristine Nelson, Cristina Maria Garrone, Karin Hansson, Ian Evans, Axel Behrens and Rocio Sancho ()
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Teodora Manea: King’s College London
Jessica Kristine Nelson: The Francis Crick Institute
Cristina Maria Garrone: King’s College London
Karin Hansson: Institute of Cancer Research
Ian Evans: The Francis Crick Institute
Axel Behrens: The Francis Crick Institute
Rocio Sancho: King’s College London

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38146-9

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