Calcineurin/NFAT signalling regulates pancreatic [beta]-cell growth and function

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From: Nature(Vol. 443, Issue 7109)
Publisher: Nature Publishing Group
Document Type: Article
Length: 4,756 words
Lexile Measure: 1460L

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Author(s): Jeremy J. Heit [1]; Åsa A. Apelqvist [1, 6]; Xueying Gu [1]; Monte M. Winslow [2]; Joel R. Neilson [3]; Gerald R. Crabtree [1, 4]; Seung K. Kim (corresponding author) [1, 5]

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 unclear [1, 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 responses [3], but the roles of this pathway in [beta]-cells in vivo are not understood. Here we show that mice with a [beta]-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 ( Cnb1 ), develop age-dependent diabetes characterized by decreased [beta]-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, [beta]-cells lacking Cnb1 have a reduced expression of established regulators of [beta]-cell proliferation [1, 4, 5]. Conditional expression of active NFATc1 in Cnb1-deficient [beta]-cells rescues these defects and prevents diabetes. In normal adult [beta]-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases [beta]-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for [beta]-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 [beta]-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.

Physiological and developmental cues in cells such as lymphocytes, myocytes and neurons stimulate intracellular Ca2+ transients, leading to dephosphorylation and nuclear translocation of the cytoplasmic subunits of NFAT transcription complexes (NFATc) [6, 7, 8]. [beta]-cell mitogens and secretion stimulators such as glucose, insulin and glucagon-like peptide-1 (GLP-1) promote increased intracellular Ca 2+ concentrations, indicating that calcineurin/NFAT signalling might regulate [beta]-cell proliferation and secretion [1]. Consistent with this possibility is the observation that all four NFATc proteins (NFATc1-4) are expressed in [beta]-cells as well as in other hormone-producing islet cells and a subset of acinar cells (Fig. 1a-d and Supplementary Fig. 1). Cnb1 regulates the activity of the calcineurin phosphatase complex and is required for the activation of all NFATc proteins [6, 7]. We therefore constructed mice with specific inactivation of Cnb1 in [beta]-cells. Mice with Cnb1 floxed (Cnb1 f ) and null (Cnb1 [DELTA] ) alleles [8, 9] or with a transgene expressing Cre recombinase from the rat insulin promoter (RIP; ref. 10) were used to generate RIP-Cre ; Cnb1 [DELTA]/f ([beta]Cnb1KO) mice. Littermate control islets expressed Cnb1 messenger RNA (Fig. 1e), but [beta]Cnb1KO islets lacked Cnb1 mRNA (Fig. 1e), which is consistent with genomic Cnb1 f allele recombination in islets (Supplementary Fig. 2). In contrast, no RIP- Cre activity was detected in other tissues, including the brain (Supplementary Fig. 2). As expected, the accumulation of NFATc1 in [beta]-cell nuclei was reduced in [beta]Cnb1KO mice, in contrast to the predominantly nuclear localization of NFATc1 in littermate controls (Fig. 1f, g).

To study the consequences of Cnb1 inactivation in [beta]Cnb1KO...

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Gale Document Number: GALE|A185447859