The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue PLoS Genetics Année : 2013

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

Christophe Ravaud
  • Fonction : Auteur
Gunter Leuckx
  • Fonction : Auteur
Sandra Lacas-Gervais
Fanny Burel-Vandenbos
  • Fonction : Auteur
Damien Ambrosetti
Jacob Hecksher-Sorensen
  • Fonction : Auteur
Philippe Ravassard
Harry Heimberg
  • Fonction : Auteur
Ahmed Mansouri
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-00968570 , version 1 (01-04-2014)

Identifiants

Citer

Monica Courtney, Elisabet Gjernes, Noémie Druelle, Christophe Ravaud, Andhira Vieira, et al.. The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells.. PLoS Genetics, 2013, 9 (10), pp.e1003934. ⟨10.1371/journal.pgen.1003934⟩. ⟨hal-00968570⟩
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