title: Polyamine biosynthesis is critical for growth and differentiation of the pancreas.
abstract: The pancreas, in most studied vertebrates, is a compound organ with both exocrine and endocrine functions. The exocrine compartment makes and secretes digestive enzymes, while the endocrine compartment, organized into islets of Langerhans, produces hormones that regulate blood glucose. High concentrations of polyamines, which are aliphatic amines, are reported in exocrine and endocrine cells, with insulin-producing β cells showing the highest concentrations. We utilized zebrafish as a model organism, together with pharmacological inhibition or genetic manipulation, to determine how polyamine biosynthesis functions in pancreatic organogenesis. We identified that inhibition of polyamine biosynthesis reduces exocrine pancreas and β cell mass, and that these reductions are at the level of differentiation. Moreover, we demonstrate that inhibition of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, phenocopies inhibition or knockdown of the enzyme deoxyhypusine synthase (DHS). These data identify that the pancreatic requirement for polyamine biosynthesis is largely mediated through a requirement for spermidine for the downstream posttranslational modification of eIF5A by its enzymatic activator DHS, which in turn impacts mRNA translation. Altogether, we have uncovered a role for polyamine biosynthesis in pancreatic organogenesis and identified that it may be possible to exploit polyamine biosynthesis to manipulate pancreatic cell differentiation.
authors: Department of Pediatrics, Indiana University School of Medicine, USA.|Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, USA.
authors: Teresa L
authors: TL
authors: Mastracci
authors: Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, USA.
authors: Morgan A
authors: MA
authors: Robertson
authors: Department of Pediatrics, Indiana University School of Medicine, USA.|Department of Physiology, Indiana University School of Medicine, USA.|Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, USA.
authors: Raghavendra G
authors: RG
authors: Mirmira
authors: Department of Pediatrics, Indiana University School of Medicine, USA.|Department of Physiology, Indiana University School of Medicine, USA.|Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, USA.
authors: Ryan M
authors: RM
authors: Anderson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology; D060172:Morpholinos / Q000494:pharmacology; D009955:Ornithine Decarboxylase / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D010179:Pancreas / Q000166:cytology* / Q000254:growth & development*; D010641:Phenotype; D011073:Polyamines / Q000378:metabolism*; D013095:Spermidine / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics
chemical_list: D060172:Morpholinos; D011073:Polyamines; D000587:Oxidoreductases Acting on CH-NH Group Donors; C063507:deoxyhypusine synthase; D009955:Ornithine Decarboxylase; D013095:Spermidine; D000518:Eflornithine