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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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References

  1. Heit, J. J., Karnik, S. K. & Kim, S. K. Intrinsic regulators of pancreatic β-cell proliferation. Annu. Rev. Cell Dev. Biol 22, 311–338 (2006)

    Article  CAS  Google Scholar 

  2. Cozar-Castellano, I. et al. Molecular control of cell cycle progression in the pancreatic β-cell. Endocr. Rev. 27, 356–370 (2006)

    Article  CAS  Google Scholar 

  3. Weir, M. R. & Fink, J. C. Risk for posttransplant diabetes mellitus with current immunosuppressive medications. Am. J. Kidney Dis. 34, 1–13 (1999)

    Article  CAS  Google Scholar 

  4. Georgia, S. & Bhushan, A. β cell replication is the primary mechanism for maintaining postnatal β cell mass. J. Clin. Invest. 114, 963–968 (2004)

    Article  CAS  Google Scholar 

  5. Kushner, J. A. et al. Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth. Mol. Cell. Biol. 25, 3752–3762 (2005)

    Article  CAS  Google Scholar 

  6. Graef, I. A., Chen, F., Chen, L., Kuo, A. & Crabtree, G. R. Signals transduced by Ca2+/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell 105, 863–875 (2001)

    Article  CAS  Google Scholar 

  7. Crabtree, G. R. & Olson, E. N. NFAT signaling: choreographing the social lives of cells. Cell 109 (Suppl.), S67–S79 (2002)

    Article  CAS  Google Scholar 

  8. Neilson, J. R., Winslow, M. M., Hur, E. M. & Crabtree, G. R. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20, 255–266 (2004)

    Article  CAS  Google Scholar 

  9. Winslow, M. M., Gallo, E. M., Neilson, J. R. & Crabtree, G. R. The calcineurin phosphatase complex modulates immunogenic B cell responses. Immunity 24, 141–152 (2006)

    Article  CAS  Google Scholar 

  10. Herrera, P. L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127, 2317–2322 (2000)

    CAS  PubMed  Google Scholar 

  11. Lawrence, M. C., Bhatt, H. S., Watterson, J. M. & Easom, R. A. Regulation of insulin gene transcription by a Ca2+-responsive pathway involving calcineurin and nuclear factor of activated T cells. Mol. Endocrinol. 15, 1758–1767 (2001)

    Article  CAS  Google Scholar 

  12. Lawrence, M. C., Bhatt, H. S. & Easom, R. A. NFAT regulates insulin gene promoter activity in response to synergistic pathways induced by glucose and glucagon-like peptide-1. Diabetes 51, 691–698 (2002)

    Article  CAS  Google Scholar 

  13. Lawrence, M. C., McGlynn, K., Park, B. H. & Cobb, M. H. ERK1/2-dependent activation of transcription factors required for acute and chronic effects of glucose on the insulin gene promoter. J. Biol. Chem. 280, 26751–26759 (2005)

    Article  CAS  Google Scholar 

  14. Redmon, J. B., Olson, L. K., Armstrong, M. B., Greene, M. J. & Robertson, R. P. Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J. Clin. Invest. 98, 2786–2793 (1996)

    Article  CAS  Google Scholar 

  15. Thorens, B., Guillam, M. T., Beermann, F., Burcelin, R. & Jaquet, M. Transgenic reexpression of GLUT1 or GLUT2 in pancreatic β cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. J. Biol. Chem. 275, 23751–23758 (2000)

    Article  CAS  Google Scholar 

  16. O'Rahilly, S., Barroso, I. & Wareham, N. J. Genetic factors in type 2 diabetes: the end of the beginning? Science 307, 370–373 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Rane, S. G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nature Genet. 22, 44–52 (1999)

    Article  CAS  Google Scholar 

  18. Laybutt, D. R. et al. Overexpression of c-Myc in β-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 51, 1793–1804 (2002)

    Article  CAS  Google Scholar 

  19. Pelengaris, S., Khan, M. & Evan, G. I. Suppression of Myc-induced apoptosis in β cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002)

    Article  CAS  Google Scholar 

  20. Miyazaki, J. et al. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 127, 126–132 (1990)

    Article  CAS  Google Scholar 

  21. Baksh, S. et al. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol. Cell 10, 1071–1081 (2002)

    Article  CAS  Google Scholar 

  22. Beals, C. R., Clipstone, N. A., Ho, S. N. & Crabtree, G. R. Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction. Genes Dev. 11, 824–834 (1997)

    Article  CAS  Google Scholar 

  23. Winslow, M. M. et al. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev. Cell 10, 771–782 (2006)

    Article  CAS  Google Scholar 

  24. Smart, N. G. et al. Conditional expression of Smad7 in pancreatic β cells disrupts TGF-β signaling and induces reversible diabetes mellitus. PLoS Biol. 4, e39 (2006)

    Article  ADS  Google Scholar 

  25. Screaton, R. A. et al. The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119, 61–74 (2004)

    Article  CAS  Google Scholar 

  26. Arron, J. R. et al. NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441, 595–600 (2006)

    Article  ADS  CAS  Google Scholar 

  27. Bruning, J. C. et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88, 561–572 (1997)

    Article  CAS  Google Scholar 

  28. Kulkarni, R. N. et al. PDX-1 haploinsufficiency limits the compensatory islet hyperplasia that occurs in response to insulin resistance. J. Clin. Invest. 114, 828–836 (2004)

    Article  CAS  Google Scholar 

  29. Karnik, S. K. et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc. Natl Acad. Sci. USA 102, 14659–14664 (2005)

    Article  ADS  CAS  Google Scholar 

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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 information

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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