class="head no_bottom_margin" id="sec1title">IntroductionThe pancreas comprises an exocrine component (ductal and acinar cells) and an endocrine component (β cells, α cells, δ cells, pancreatic polypeptide-positive [pp] cells, and ε cells). The endocrine cells are organized in defined islet structures embedded in the acinar compartment, which function as key regulators of carbohydrate metabolism (). The autoimmune disease Type 1 diabetes irreversibly destroys insulin-secreting β cells in pancreatic islets, resulting in a lack of insulin production and hyperglycemia (). Treatment is most commonly with insulin injections, but the degree of glycemic control with this approach does not compare to functional pancreatic β cells. Regenerative β cell treatments in diabetic patients could allow for the long-term restoration of normal glycemic control and thus represent a potentially curative therapy ().The generation of new pancreatic β cells is being pursued on several fronts in vitro, including differentiation of induced pluripotent stem cells (iPSCs) and reprogramming of other pancreatic cell types (). Regenerating pancreatic β cells in situ is an attractive alternative to these approaches, driven by evidence of spontaneous β cell neogenesis in the adult pancreas (). β cell regeneration during adulthood is very limited but can be achieved experimentally using pancreatic duct ligation in mice () and pancreatectomy in rats (). Inducible depletion of acinar and islet cells with diphtheria toxin showed that duct cells can give rise to both acinar and endocrine cells (). Thus, ductal cells in the adult pancreas show a latent propensity for β cell generation. Additionally, genetic approaches have converted other pancreatic cell types into β cells. Adenoviral overexpression of the three transcription factors neurogenin-3 (Ngn3), Maf1a, and Pdx1 is sufficient to convert adult acinar cells into β cells (), and overexpression of Pax4 converts glucagon-producing α cells into β cells (). However, the capacity for β cell neogenesis in the normal adult pancreas, and the regulatory events surrounding it, remain largely unknown.Ngn3 is the earliest factor that specifically regulates the development of the endocrine compartment in the embryonic pancreas (). Ngn3−/− mice completely lack endocrine islet development (), and transgenic overexpression of Ngn3 activates an islet differentiation program in the embryo and in cultured pancreatic ductal cell lines (). In the adult pancreas, Ngn3 expression is very limited, but levels rise during β cell neogenesis induced by pancreatic duct ligation, where Ngn3 is required for β cell replenishment (). Moreover, expansion of Ngn3+ cells bordering the ducts contributes to the β cell expansion observed when overexpressing Pax4 (href="#bib1" rid="bib1" class=" bibr popnode">Al-Hasani et al., 2013), indicating that manipulation of Ngn3 levels and/or activity may be beneficial for regeneration therapies. Ngn3 is a highly unstable protein (href="#bib44" rid="bib44" class=" bibr popnode">Roark et al., 2012), and the level and timing of its expression must be precisely controlled to ensure the correct production of β cells, but the details of its posttranslational regulation remain elusive.Fbw7 (F-box and WD-40 domain protein 7) is the substrate recognition component of an evolutionarily conserved SCF (complex of SKP1, CUL1, and F-box protein)-type ubiquitin ligase. SCF(Fbw7) degrades proteins that function in cellular growth and division pathways, including c-Myc, cyclin E, Notch, and c-Jun (href="#bib56" rid="bib56" class=" bibr popnode">Welcker and Clurman, 2008). Emerging evidence shows that Fbw7 controls stem cell self-renewal, cell fate decisions, survival, and multipotency in numerous tissues, including the hematopoietic (href="#bib26" rid="bib26" class=" bibr popnode">Iriuchishima et al., 2011) and nervous systems (href="#bib24" rid="bib24 bib31" class=" bibr popnode">Hoeck et al., 2010; Matsumoto et al., 2011), liver (href="#bib40" rid="bib40" class=" bibr popnode">Onoyama et al., 2011), and intestine (href="#bib45" rid="bib45" class=" bibr popnode">Sancho et al., 2010). This suggests that Fbw7 has a crucial function in fundamental cell differentiation processes.Here, we show that Fbw7 contributes to the regulation of Ngn3 stability, and loss of Fbw7 induces a direct ductal-to-β cell differentiation in the adult pancreas. Our study not only reveals a role for Fbw7 in pancreatic cell fate determination and identifies Ngn3 as a target of Fbw7 but also demonstrates that ductal cells can be induced to alter their identity in the adult pancreas in the absence of injury to the organ with a single genetic change.
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