biostudies-literatureManea TCancer Research UKMedical Research CouncilThe Francis Crick InstituteWellcome TrustEngineering and Physical Sciences Research Council2457https://www.ebi.ac.uk/biostudies/studies/S-EPMC10147604biostudies-literatureUnknown14(1)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 Nature communicationsUSP7 controls NGN3 stability and pancreatic endocrine lineage development.PMC10147604MR/T015470/1FC001039MR/S000011/1218461/Z/19/ZEP/T003103/1CC2015215138/Z/18/ZBehrens AGarrone CMManea TNelson JKEvans IHansson KSancho RfalseUSP7 controls NGN3 stability and pancreatic endocrine lineage development.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 2023-01-01T00:00:00Z2023 Apr2026-07-14T20:08:41.635Z2025-02-19T04:46:20.823ZS-EPMC101476043711718510.1038/s41467-023-38146-9