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

Nature volume 443, pages 345–349 (2006)Cite this article

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.

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Figure 1: NFATc proteins are expressed in β-cells, and Cnb1 deletion results in NFATc1 mislocalization.
Figure 2: βCnb1KO mice develop age-dependent diabetes mellitus.
Figure 3: NFATc controls the expression of essential β-cell factors in βCnb1KO mice.
Figure 4: Active NFATc1 induces the expression of essential β-cell markers, increases β-cell proliferation and mass, and induces hyperinsulinaemia.
Figure 5: Expression of active NFATc1 in Cnb1-deficient β-cells restores β-cell proliferation, mass and function, and prevents diabetes mellitus.

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Acknowledgements

We thank G. McLean, M. McLane and J. Morillo for technical assistance; R. Kulkarni, A. Xu and G. Barsh for advice; and members of the Crabtree and Kim laboratories for discussions and critical readings of this manuscript. J.J.H. is a student in the Stanford Medical Scientist Training Program and is additionally supported by an American Diabetes Association (ADA) Medical Scholars grant. M.M.W. is supported by a Stanford graduate fellowship and a Howard Hughes Medical Institute (HHMI) Predoctoral Fellowship. This work was supported by awards to G.R.C. from HHMI and the NIH, and to S.K.K. from the NIH, the Biomedical Scholars Program of the Pew Charitable Trusts, and the Stephen and Caroline Kaufer Fund for Neuroendocrine Tumor Research. Author Contributions J.J.H., Å.A.A. and S.K.K. generated the hypotheses and designed the experiments. J.R.N., M.M.W. and G.R.C. generated and helped validate Cnb1f, Cnb1Δ and TRE-NFATc1nuc transgenic mice. X.G., Å.A.A. and J.J.H. performed experiments. J.J.H. and S.K.K. wrote the manuscript.

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Author notes

  1. Åsa A. Apelqvist

    Present address: MRC Centre for Developmental Neurobiology, King's College London, London, WC2R 2LS, UK

Authors and Affiliations

  1. Department of Developmental Biology,

    Jeremy J. Heit, Åsa A. Apelqvist, Xueying Gu, Gerald R. Crabtree & Seung K. Kim

  2. Program in Immunology,

    Monte M. Winslow

  3. Department of Microbiology and Immunology,

    Joel R. Neilson

  4. Department of Pathology and Howard Hughes Medical Institute,

    Gerald R. Crabtree

  5. Department of Medicine (Oncology Division), Stanford University, Stanford, California, 94305, USA

    Seung K. Kim

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Correspondence to Seung K. Kim.

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Supplementary Figures

This file contains Supplementary Figures 1–11 and Supplementary Table 1 (a list of primers used in this study). (PDF 1194 kb)

Supplementary Methods

This file contains detailed methods and protocols for the experiments in this study. (DOC 50 kb)

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Heit, J., Apelqvist, Å., Gu, X. et al. Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function. Nature 443, 345–349 (2006). https://doi.org/10.1038/nature05097

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