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Published on: August 7, 2015
Neonatal β cell development in mice and humans is regulated by calcineurin/NFAT
William R Goodyer1, Xueying Gu, Yinghua Liu
1Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract:
Little is known about the mechanisms governing neonatal growth and maturation of organs. Here we demonstrate that calcineurin/Nuclear Factor of Activated T cells (Cn/NFAT) signaling regulates neonatal pancreatic development in mouse and human islets. Inactivation of calcineurin b1 (Cnb1) in mouse islets impaired dense core granule biogenesis, decreased insulin secretion, and reduced cell proliferation and mass, culminating in lethal diabetes. Pancreatic β cells lacking Cnb1 failed to express genes revealed to be direct NFAT targets required for replication, insulin storage, and secretion. In contrast, glucokinase activation stimulated Cn-dependent expression of these genes. Calcineurin inhibitors, such as tacrolimus, used for human immunosuppression, induce diabetes. Tacrolimus exposure reduced Cn/NFAT-dependent expression of factors essential for insulin dense core granule formation and secretion and neonatal β cell proliferation, consistent with our genetic studies. Discovery of conserved pathways regulating β cell maturation and proliferation suggests new strategies for controlling β cell growth or replacement in human islet diseases.
Insights
Calcineurin/Nuclear Factor of Activated T cells (Cn/NFAT) signaling is crucial for neonatal pancreatic development and insulin secretion. Its disruption leads to diabetes, highlighting pathways for islet cell growth and disease treatment.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Signaling
Background:
- Mechanisms of neonatal organ growth and maturation are poorly understood.
- Pancreatic islet development and function are critical for glucose homeostasis.
Purpose of the Study:
- To investigate the role of calcineurin/Nuclear Factor of Activated T cells (Cn/NFAT) signaling in neonatal pancreatic development.
- To identify molecular targets regulated by Cn/NFAT in pancreatic beta cells.
Main Methods:
- Genetic inactivation of calcineurin b1 (Cnb1) in mouse islets.
- Analysis of gene expression, insulin secretion, cell proliferation, and islet mass.
- Assessment of tacrolimus effects on neonatal beta cell function.
Main Results:
- Inactivation of Cnb1 in mouse islets impaired dense core granule biogenesis, insulin secretion, and beta cell proliferation and mass, leading to lethal diabetes.
- Cnb1-deficient beta cells failed to express key NFAT target genes for replication and insulin handling.
- Glucokinase activation promoted Cn-dependent expression of these essential genes.
- Tacrolimus exposure mimicked genetic findings, reducing Cn/NFAT-dependent factors for insulin secretion and beta cell proliferation.
Conclusions:
- Cn/NFAT signaling is a conserved pathway essential for neonatal pancreatic beta cell maturation, proliferation, and function.
- Understanding these pathways offers potential therapeutic strategies for human islet diseases and diabetes.
- Calcineurin inhibitors like tacrolimus pose a risk for diabetes due to their impact on beta cell function.
