Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
- The Hadassah-Hebrew University Medical Center, Israel
- The Hebrew University-Hadassah Medical School, Israel
- Miller School of Medicine, University of Miami, United States
Abstract
Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal β-cell growth and differentiation. Importantly, restoration of mTORC1 activity in neonate β-cells was sufficient to rescue postnatal β-cell growth, and to improve diabetes. We propose a scenario for the development of permanent neonatal diabetes, possibly also common forms of diabetes, where early-life events inducing ER stress affect β-cell mass expansion due to mTOR inhibition.
Data availability
The RNA-seq data is available through NCBI. The accession number is: GSE114927
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RNAseq analysis of whole islets from pre-weaning wild type and Akita miceGene Expression Omnibus, GSE114927.
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RNA profiling of P16ink4a-expressing pancreatic beta-cellsGene Expression Omnibus, GSE76992.
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Identification of Nkx6.1 regulated genes in mature pancreatic isletsGene Expression Omnibus, GSE40470.
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Chromatin immunoprecipitation of mouse MIN6 pancreatic beta cells to identify Pdx1 targetsArrayExpress Archive of Functional Genomics Data, E-MTAB-134.
Article and author information
Author details
Funding
Israel Science Foundation (ISF-347/12)
- Gil Leibowitz
Israel Science Foundation (ISF-1563/14)
- Gil Leibowitz
Israel Science Foundation (2323/17)
- Gil Leibowitz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Hebrew University. All of the animals were handled according to approved institutional animal care and use committee of the Hebrew University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Hebrew University (Permit Number: MD-17-15065-4). Every effort was made to minimize animal suffering.
Copyright
© 2018, Riahi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibition of mTORC1 by ER stress impairs neonatal β-cell expansion and predisposes to diabetes in the Akita mouse
eLife 7:e38472.
https://doi.org/10.7554/eLife.38472
Further reading
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- Stem Cells and Regenerative Medicine
Exploring how proliferation and maturation of beta-cells can be impaired after birth will shed light on the origins of various forms of diabetes.
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- Cancer Biology
- Cell Biology
PML, a multifunctional protein, is crucial for forming PML-nuclear bodies involved in stress responses. Under specific conditions, PML associates with nucleolar caps formed after RNA polymerase I (RNAPI) inhibition, leading to PML-nucleolar associations (PNAs). This study investigates PNAs-inducing stimuli by exposing cells to various genotoxic stresses. We found that the most potent inducers of PNAs introduced topological stress and inhibited RNAPI. Doxorubicin, the most effective compound, induced double-strand breaks (DSBs) in the rDNA locus. PNAs co-localized with damaged rDNA, segregating it from active nucleoli. Cleaving the rDNA locus with I-PpoI confirmed rDNA damage as a genuine stimulus for PNAs. Inhibition of ATM, ATR kinases, and RAD51 reduced I-PpoI-induced PNAs, highlighting the importance of ATM/ATR-dependent nucleolar cap formation and homologous recombination (HR) in their triggering. I-PpoI-induced PNAs co-localized with rDNA DSBs positive for RPA32-pS33 but deficient in RAD51, indicating resected DNA unable to complete HR repair. Our findings suggest that PNAs form in response to persistent rDNA damage within the nucleolar cap, highlighting the interplay between PML/PNAs and rDNA alterations due to topological stress, RNAPI inhibition, and rDNA DSBs destined for HR. Cells with persistent PNAs undergo senescence, suggesting PNAs help avoid rDNA instability, with implications for tumorigenesis and aging.
