The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells

PLoS Genet. 2013 Oct;9(10):e1003934. doi: 10.1371/journal.pgen.1003934. Epub 2013 Oct 31.

Abstract

Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing β-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 α-cells is sufficient to promote the conversion of adult α-cells into β-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 β-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 α-cell-mediated β-like cell neogenesis. Importantly, the loss of Arx in α-cells is sufficient to regenerate a functional β-cell mass and thereby reverse diabetes following toxin-induced β-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / therapy
  • Disease Models, Animal
  • Gene Expression Regulation
  • Glucagon / genetics
  • Glucagon / metabolism
  • Glucagon-Secreting Cells / metabolism
  • Glucagon-Secreting Cells / pathology
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics*
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice, Transgenic
  • Paired Box Transcription Factors / genetics
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*

Substances

  • ARX protein, mouse
  • Homeodomain Proteins
  • Paired Box Transcription Factors
  • Pax4 protein, mouse
  • Transcription Factors
  • Glucagon

Grant support

This work was supported by the Juvenile Diabetes Research foundation (17-2011-16, 2-2010-567, 26-2008-639, 17-2013-426), the INSERM AVENIR program, the INSERM, the European Research Council (StG-2011-281265) the FMR (DRC20091217179), the ANR/BMBF (2009 GENO 105 01/01KU0906), the “Investments for the Future” LABEX SIGNALIFE (ANR-11-LABX-0028-01), the Max-Planck Society, Club Isatis, Mr and Mrs Dorato, the Fondation Générale de Santé, the Foundation Schlumberger pour l'Education et la Recherche, the DON Foundation (www.sdon.nl), and the Fund for Scientific Research-Flanders. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.