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  The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells.

Courtney, M., Gjernes, E., Druelle, N., Ravaud, C., Vieira, A., Ben-Othman, N., et al. (2013). The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genetics, 9(10): e1003934. doi:10.1371/journal.pgen.1003934.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0015-8811-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CEF4-E
Genre: Journal Article

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Courtney, M., Author
Gjernes, E., Author
Druelle, N., Author
Ravaud, C., Author
Vieira, A., Author
Ben-Othman, N., Author
Pfeifer, A., Author
Avolio, F., Author
Leuckx, G., Author
Lacas-Gervais, S., Author
Burel-Vandenbos, F., Author
Ambrosetti, D., Author
Hecksher-Sorensen, J., Author
Ravassard, P., Author
Heimberg, H., Author
Mansouri, A.1, Author              
Collombat, P., Author
Affiliations:
1Research Group of Molecular Cell Differentiation, MPI for biophysical chemistry, Max Planck Society, ou_578588              

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 Abstract: 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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Language(s): eng - English
 Dates: 2013-10-31
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1371/journal.pgen.1003934
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Title: PLoS Genetics
Source Genre: Journal
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Pages: - Volume / Issue: 9 (10) Sequence Number: e1003934 Start / End Page: - Identifier: -