Aristaless-related homeobox (Arx) was recently demonstrated to be involved in pancreatic α cell fate specification while simultaneously repressing the β and δ cell lineages. To establish whether Arx is not only necessary, but also sufficient to instruct the α 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 β and δ cells. Concurrently, a remarkable increase in the number of cells displaying α cell or, strikingly, pancreatic polypeptide (PP) cell features was observed. Notably, the ectopic expression of Arx induced in embryonic or adult β cells led to a loss of the β cell phenotype and a concomitant increase in a number of cells with α 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 β 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.
Patrick Collombat, Jacob Hecksher-Sørensen, Jens Krull, Joachim Berger, Dietmar Riedel, Pedro L. Herrera, Palle Serup, Ahmed Mansouri
Title and authors | Publication | Year |
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The Beta Cell in Type 2 Diabetes
AA Christensen, M Gannon |
Current Diabetes Reports | 2019 |
Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity
J Liu, A Banerjee, CA Herring, J Attalla, R Hu, Y Xu, Q Shao, AJ Simmons, PK Dadi, S Wang, DA Jacobson, B Liu, E Hodges, KS Lau, G Gu |
Developmental Cell | 2019 |
Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors
P Cejas, Y Drier, KM Dreijerink, LA Brosens, V Deshpande, CB Epstein, EB Conemans, FH Morsink, MK Graham, GD Valk, MR Vriens, CF Castillo, CR Ferrone, T Adar, M Bowden, HJ Whitton, AD Silva, A Font-Tello, HW Long, E Gaskell, N Shoresh, CM Heaphy, E Sicinska, MH Kulke, DC Chung, BE Bernstein, RA Shivdasani |
Nature Medicine | 2019 |