USP7 controls NGN3 stability and pancreatic endocrine lineage development
Teodora Manea1, Jessica Kristine Nelson2,3, Cristina Maria Garrone1
1Centre for Gene Therapy and Regenerative Medicine, King's College London, London, UK.
Nature Communications
|April 28, 2023
Summary
The deubiquitylating enzyme USP7 stabilizes the key transcription factor Neurogenin 3 (NGN3), crucial for beta-cell development. Targeting this USP7-NGN3 interaction may offer new therapies for diabetes.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Medicine
Background:
- Beta-cell development is critical for managing diabetes.
- Neurogenin 3 (NGN3) is a key transcription factor for endocrine cell differentiation.
- Understanding NGN3 regulation is vital for therapeutic strategies.
Purpose of the Study:
- To identify NGN3 binding partners.
- To elucidate the role of USP7 in NGN3 regulation and beta-cell development.
- To explore therapeutic potential of the USP7-NGN3 axis.
Main Methods:
- Screening for NGN3 binding partners.
- In vivo studies using conditional Usp7 knockout mice.
- In vitro studies using human induced pluripotent stem cell (iPSC) models.
Main Results:
- USP7 was identified as a binding partner of NGN3.
- USP7 deubiquitinates and stabilizes NGN3.
- Usp7 knockout in mice led to reduced islet formation and hyperglycemia.
- USP7 inhibition in human iPSCs impaired beta-cell differentiation.
Conclusions:
- The USP7-NGN3 axis is essential for pancreatic endocrine development.
- USP7 is a critical regulator of NGN3 stability and function.
- Targeting USP7 presents a potential therapeutic strategy for diabetes treatment.
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