Journal
PLOS GENETICS
Volume 9, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003934
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Funding
- Juvenile Diabetes Research foundation [17-2011-16, 2-2010-567, 26-2008-639, 17-2013-426]
- INSERM AVENIR program
- INSERM
- European Research Council [StG-2011-281265]
- FMR [DRC20091217179]
- ANR/BMBF [GENO 105 01/01KU0906]
- Investments for the Future LABEX SIGNALIFE [ANR-11-LABX-0028-01]
- Max-Planck Society
- Club Isatis
- Fondation Generale de Sante
- Foundation Schlumberger pour l'Education et la Recherche
- DON Foundation
- Fund for Scientific Research-Flanders
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Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulinproducing beta-like cells through the ectopic expression of a single gene, Pax4. Here, combining conditional loss-of-function and lineage tracing approaches, we show that the selective inhibition of the Arx gene in alpha-cells is sufficient to promote the conversion of adult alpha-cells into beta-like cells at any age. Interestingly, this conversion induces the continuous mobilization of duct-lining precursor cells to adopt an endocrine cell fate, the glucagon(+) cells thereby generated being subsequently converted into beta-like cells upon Arx inhibition. Of interest, through the generation and analysis of Arx and Pax4 conditional double-mutants, we provide evidence that Pax4 is dispensable for these regeneration processes, indicating that Arx represents the main trigger of alpha-cell-mediated beta-like cell neogenesis. Importantly, the loss of Arx in alpha-cells is sufficient to regenerate a functional beta-cell mass and thereby reverse diabetes following toxin-induced beta-cell depletion. Our data therefore suggest that strategies aiming at inhibiting the expression of Arx, or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes.
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