title: The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells.
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.
authors.affiliation: Université de Nice Sophia Antipolis, iBV, UMR 7277, Nice, France ; Inserm, iBV, U1091, Nice, France ; CNRS, iBV, UMR 7277, Nice, France.
authors.forename: Monica
authors.initials: M
authors.lastname: Courtney
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gjernes
authors.forename: Noémie
authors.initials: N
authors.lastname: Druelle
authors.forename: Christophe
authors.initials: C
authors.lastname: Ravaud
authors.forename: Andhira
authors.initials: A
authors.lastname: Vieira
authors.forename: Nouha
authors.initials: N
authors.lastname: Ben-Othman
authors.forename: Anja
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Fabio
authors.initials: F
authors.lastname: Avolio
authors.forename: Gunter
authors.initials: G
authors.lastname: Leuckx
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.forename: Fanny
authors.initials: F
authors.lastname: Burel-Vandenbos
authors.forename: Damien
authors.initials: D
authors.lastname: Ambrosetti
authors.forename: Jacob
authors.initials: J
authors.lastname: Hecksher-Sorensen
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005934:Glucagon / Q000235:genetics / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D051761:Paired Box Transcription Factors / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C469265:ARX protein, mouse; D018398:Homeodomain Proteins; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; D014157:Transcription Factors; D005934:Glucagon