Essential role of the small GTPase Ran in postnatal pancreatic islet development

Fang Xia, Takehiko Dohi, Nina M. Martin, Christopher M. Raskett, Qin Liu, Dario C. Altieri

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere27879
JournalPloS one
Volume6
Issue number11
DOIs
StatePublished - Nov 17 2011

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Monomeric GTP-Binding Proteins
islets of Langerhans
guanosinetriphosphatase
Islets of Langerhans
Transgenic Mice
genetically modified organisms
Insulin
insulin
mice
mutants
Deregulation
GTP Phosphohydrolases
Cell proliferation
Medical problems
Insulinoma
Small Interfering RNA
Rats
Homeobox Genes
Transcription Factors
hyperglycemia

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Xia, F., Dohi, T., Martin, N. M., Raskett, C. M., Liu, Q., & Altieri, D. C. (2011). Essential role of the small GTPase Ran in postnatal pancreatic islet development. PloS one, 6(11), [e27879]. https://doi.org/10.1371/journal.pone.0027879
Xia, Fang ; Dohi, Takehiko ; Martin, Nina M. ; Raskett, Christopher M. ; Liu, Qin ; Altieri, Dario C. / Essential role of the small GTPase Ran in postnatal pancreatic islet development. In: PloS one. 2011 ; Vol. 6, No. 11.
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Essential role of the small GTPase Ran in postnatal pancreatic islet development. / Xia, Fang; Dohi, Takehiko; Martin, Nina M.; Raskett, Christopher M.; Liu, Qin; Altieri, Dario C.

In: PloS one, Vol. 6, No. 11, e27879, 17.11.2011.

Research output: Contribution to journalArticle

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