Conditional expression of Smad7 in pancreatic β cells disrupts TGF-β signaling and induces reversible diabetes mellitus

Nora G. Smart, Åsa A. Apelqvist, Xueying Gu, Erin B. Harmon, James N. Topper, Raymond J. MacDonald, Seung K. Kim

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Identification of signaling pathways that maintain and promote adult pancreatic islet functions will accelerate our understanding of organogenesis and improve strategies for treating diseases like diabetes mellitus. Previous work has implicated transforming growth factor-β (TGF-β) signaling as an important regulator of pancreatic islet development, but has not established whether this signaling pathway is required for essential islet functions in the adult pancreas. Here we describe a conditional system for expressing Smad7, a potent inhibitor of TGF-β signaling, to identify distinct roles for this pathway in adult and embryonic β cells. Smad7 expression in Pdx1 + embryonic pancreas cells resulted in striking embryonic β cell hypoplasia and neonatal lethality. Conditional expression of Smad7 in adult Pdx1+ cells reduced detectable β cell expression of MafA, menin, and other factors that regulate β cell function. Reduced pancreatic insulin content and hypoinsulinemia produced overt diabetes that was fully reversed upon resumption of islet TGF-β signaling. Thus, our studies reveal that TGF-β signaling is crucial for establishing and maintaining defining features of mature pancreatic β cells. Copyright:

Original languageEnglish (US)
Pages (from-to)200-209
Number of pages10
JournalPLoS biology
Volume4
Issue number2
DOIs
StatePublished - Feb 2006

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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