title: Essential role of the small GTPase Ran in postnatal pancreatic islet development.
abstract: The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin(+) β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo.
authors: Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors: Fang
authors: F
authors: Xia
authors: Takehiko
authors: T
authors: Dohi
authors: Nina M
authors: NM
authors: Martin
authors: Christopher M
authors: CM
authors: Raskett
authors: Qin
authors: Q
authors: Liu
authors: Dario C
authors: DC
authors: Altieri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D003920:Diabetes Mellitus / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D006946:Hyperinsulinism / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000097:blood / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D020931:ran GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D007328:Insulin; C120587:RAN protein, human; D034741:RNA, Small Interfering; D004247:DNA; D020931:ran GTP-Binding Protein; D005947:Glucose