Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function

Jeremy J. Heit, Åsa A. Apelqvist, Xueying Gu, Monte M. Winslow, Joel R. Neilson, Gerald R. Crabtree and Seung K. Kim ()
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Jeremy J. Heit: Department of Developmental Biology
Åsa A. Apelqvist: Department of Developmental Biology
Xueying Gu: Department of Developmental Biology
Monte M. Winslow: Program in Immunology
Joel R. Neilson: Department of Microbiology and Immunology
Gerald R. Crabtree: Department of Developmental Biology
Seung K. Kim: Department of Developmental Biology

Nature, 2006, vol. 443, issue 7109, 345-349

Abstract: Abstract The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear1,2. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses3, but the roles of this pathway in β-cells in vivo are not understood. Here we show that mice with a β-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased β-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, β-cells lacking Cnb1 have a reduced expression of established regulators of β-cell proliferation1,4,5. Conditional expression of active NFATc1 in Cnb1-deficient β-cells rescues these defects and prevents diabetes. In normal adult β-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases β-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for β-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark β-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.

Date: 2006
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DOI: 10.1038/nature05097

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