The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional ß-like cells.
PLoS Genet
; 9(10): e1003934, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-24204325
ABSTRACT
Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing ß-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 ß-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 ß-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 ß-like cell neogenesis. Importantly, the loss of Arx in α-cells is sufficient to regenerate a functional ß-cell mass and thereby reverse diabetes following toxin-induced ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Diferenciação Celular
/
Proteínas de Homeodomínio
/
Diabetes Mellitus Tipo 1
/
Células Secretoras de Insulina
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
PLoS Genet
Assunto da revista:
GENETICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
França