title: Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression.
abstract: Aristaless-related homeobox (Arx) was recently demonstrated to be involved in pancreatic alpha cell fate specification while simultaneously repressing the beta and delta cell lineages. To establish whether Arx is not only necessary, but also sufficient to instruct the alpha cell fate in endocrine progenitors, we used a gain-of-function approach to generate mice conditionally misexpressing this factor. Mice with forced Arx expression in the embryonic pancreas or in developing islet cells developed a dramatic hyperglycemia and eventually died. Further analysis demonstrated a drastic loss of beta and delta cells. Concurrently, a remarkable increase in the number of cells displaying alpha cell or, strikingly, pancreatic polypeptide (PP) cell features was observed. Notably, the ectopic expression of Arx induced in embryonic or adult beta cells led to a loss of the beta cell phenotype and a concomitant increase in a number of cells with alpha or PP cell characteristics. Combining quantitative real-time PCR and lineage-tracing experiments, we demonstrate that, in adult mice, the misexpression of Arx, rather than its overexpression, promotes a conversion of beta cells into glucagon- or PP-producing cells in vivo. These results provide important insights into the complex mechanisms underlying proper pancreatic endocrine cell allocation and cell identity acquisition.
authors.affiliation: Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark. pas@hagedorn.dk
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
authors.forename: Jacob
authors.initials: J
authors.lastname: Hecksher-Sørensen
authors.forename: Jens
authors.initials: J
authors.lastname: Krull
authors.forename: Joachim
authors.initials: J
authors.lastname: Berger
authors.forename: Dietmar
authors.initials: D
authors.lastname: Riedel
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D005934:Glucagon / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology*; D007515:Islets of Langerhans / Q000196:embryology* / Q000254:growth & development; D051379:Mice; D010191:Pancreatic Polypeptide / Q000378:metabolism*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C469265:ARX protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D010191:Pancreatic Polypeptide; D005934:Glucagon