title: An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration.
abstract: As one of the key nutrient sensors, insulin signaling plays an important role in integrating environmental energy cues with organism growth. In adult organisms, relative insufficiency of insulin signaling induces compensatory expansion of insulin-secreting pancreatic beta (β) cells. However, little is known about how insulin signaling feedback might influence neogenesis of β cells during embryonic development. Using genetic approaches and a unique cell transplantation system in developing zebrafish, we have uncovered a novel role for insulin signaling in the negative regulation of pancreatic progenitor cell differentiation. Blocking insulin signaling in the pancreatic progenitors hastened the expression of the essential β cell genes insulin and pdx1, and promoted β cell fate at the expense of alpha cell fate. In addition, loss of insulin signaling promoted β cell regeneration and destabilization of alpha cell character. These data indicate that insulin signaling constitutes a tunable mechanism for β cell compensatory plasticity during early development. Moreover, using a novel blastomere-to-larva transplantation strategy, we found that loss of insulin signaling in endoderm-committed blastomeres drove their differentiation into β cells. Furthermore, the extent of this differentiation was dependent on the function of the β cell mass in the host. Altogether, our results indicate that modulation of insulin signaling will be crucial for the development of β cell restoration therapies for diabetics; further clarification of the mechanisms of insulin signaling in β cell progenitors will reveal therapeutic targets for both in vivo and in vitro β cell generation.
authors.affiliation: Herman B Wells Center for Pediatric Research in the Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Sciences Building MS2043, Indianapolis, IN 46202, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Sciences Building MS2043, Indianapolis, IN 46202, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ye
authors.affiliation: Herman B Wells Center for Pediatric Research in the Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Sciences Building MS2043, Indianapolis, IN 46202, USA.
authors.forename: Morgan A
authors.initials: MA
authors.lastname: Robertson
authors.affiliation: Herman B Wells Center for Pediatric Research in the Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Sciences Building MS2043, Indianapolis, IN 46202, USA.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Mastracci
authors.affiliation: Herman B Wells Center for Pediatric Research in the Department of Pediatrics and the Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Sciences Building MS2043, Indianapolis, IN 46202, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Van Nuys Medical Sciences Building MS2043, Indianapolis, IN 46202, USA. Electronic address: ryanande@iu.edu.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001757:Blastomeres / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D002454:Cell Differentiation; D019070:Cell Lineage; D004707:Endoderm / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D025461:Feedback, Physiological; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology*; D011972:Receptor, Insulin / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D015534:Trans-Activators / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D011972:Receptor, Insulin
keywords: Development; IRS2; Insulin; Pancreas; Pancreatic progenitor; Pdx1; Regeneration; Zebrafish; β cell