USP7 controls NGN3 stability and pancreatic endocrine lineage development
USP7 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 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.
Adult, Animals, Humans, Mice, Basic Helix-Loop-Helix Transcription Factors/metabolism, Cell Differentiation, Islets of Langerhans/metabolism, Pancreas/metabolism, Transcription Factors/metabolism, Ubiquitin-Specific Peptidase 7/genetics
Manea, Teodora
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Nelson, Jessica Kristine
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Garrone, Cristina Maria
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Hansson, Karin
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Evans, Ian
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Behrens, Axel
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Sancho, Rocio
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28 April 2023
Manea, Teodora
b880590d-91b2-4f3c-a72a-6f3f6b480e79
Nelson, Jessica Kristine
7dc3f0c8-5a67-4467-a332-efd560a0630b
Garrone, Cristina Maria
b7f8cda5-f328-455a-a518-bbbc8d6a3c15
Hansson, Karin
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Evans, Ian
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Behrens, Axel
562a632f-5241-42aa-b554-d3c593f9b7ce
Sancho, Rocio
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Manea, Teodora, Nelson, Jessica Kristine, Garrone, Cristina Maria, Hansson, Karin, Evans, Ian, Behrens, Axel and Sancho, Rocio
(2023)
USP7 controls NGN3 stability and pancreatic endocrine lineage development.
Nature Communications, 14 (1), [2457].
(doi:10.1038/s41467-023-38146-9).
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.
Text
s41467-023-38146-9
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More information
Accepted/In Press date: 18 April 2023
Published date: 28 April 2023
Keywords:
Adult, Animals, Humans, Mice, Basic Helix-Loop-Helix Transcription Factors/metabolism, Cell Differentiation, Islets of Langerhans/metabolism, Pancreas/metabolism, Transcription Factors/metabolism, Ubiquitin-Specific Peptidase 7/genetics
Identifiers
Local EPrints ID: 505363
URI: http://eprints.soton.ac.uk/id/eprint/505363
ISSN: 2041-1723
PURE UUID: 37942330-ae9d-4e82-86d3-64122a6c01b6
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Date deposited: 07 Oct 2025 16:45
Last modified: 08 Oct 2025 02:17
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Contributors
Author:
Teodora Manea
Author:
Jessica Kristine Nelson
Author:
Cristina Maria Garrone
Author:
Karin Hansson
Author:
Ian Evans
Author:
Axel Behrens
Author:
Rocio Sancho
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