USP7 controls NGN3 stability and pancreatic endocrine lineage development
Manea, Teodora ; Nelson, Jessica Kristine ; Garrone, Cristina Maria ; Hansson, Karin LU
; Evans, Ian
; Behrens, Axel
and Sancho, Rocio
(2023)
In Nature Communications
14.
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/54905eca-9f04-45a6-8d00-f0d861c10c3f
- author
- Manea, Teodora
; Nelson, Jessica Kristine
; Garrone, Cristina Maria
; Hansson, Karin
LU
; Evans, Ian
; Behrens, Axel
and Sancho, Rocio
- publishing date
- 2023-04-28
- type
- Contribution to journal
- publication status
- published
- in
- Nature Communications
- volume
- 14
- article number
- 2457
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85156240894
- ISSN
- 2041-1723
- DOI
- 10.1038/s41467-023-38146-9
- language
- English
- LU publication?
- no
- id
- 54905eca-9f04-45a6-8d00-f0d861c10c3f
- date added to LUP
- 2025-03-31 10:04:36
- date last changed
- 2025-04-01 04:01:58
@article{54905eca-9f04-45a6-8d00-f0d861c10c3f,
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.}},
author = {{Manea, Teodora and Nelson, Jessica Kristine and Garrone, Cristina Maria and Hansson, Karin and Evans, Ian and Behrens, Axel and Sancho, Rocio}},
issn = {{2041-1723}},
language = {{eng}},
month = {{04}},
publisher = {{Nature Publishing Group}},
series = {{Nature Communications}},
title = {{USP7 controls NGN3 stability and pancreatic endocrine lineage development}},
url = {{http://dx.doi.org/10.1038/s41467-023-38146-9}},
doi = {{10.1038/s41467-023-38146-9}},
volume = {{14}},
year = {{2023}},
}