Stabilization of β-catenin impacts pancreas growth

Abstract

A recent study has shown that deletion of ␤-catenin within the pancreatic epithelium results in a loss of pancreas mass. Here, we show that ectopic stabilization of ␤-catenin within mouse pancreatic epithelium can have divergent effects on both organ formation and growth. Robust stabilization of ␤-catenin during early organogenesis drives changes in hedgehog and Fgf10 signaling and induces a loss of Pdx1 expression in early pancreatic progenitor cells. Together, these perturbations in early pancreatic specification culminate in a severe reduction of pancreas mass and postnatal lethality. By contrast, inducing the stabilized form of ␤-catenin at a later time point in pancreas development causes enhanced proliferation that results in a dramatic increase in pancreas organ size. Taken together, these data suggest a previously unappreciated temporal/spatial role for ␤-catenin signaling in the regulation of pancreas organ growth.

Wnt signaling regulates pancreatic β cell proliferation

“…14 and 26). Previously, we used mice expressing Cre-recombinase under the control of the Pdx1 promoter (24) to induce expression of ␤-cat active in adult islets, but expression of Cre-recombinase was mosaic in islet ␤ cells and did not result in significant changes in ␤ cell mass (14). In 3-month-old bitransgenic RIP-Cre, ␤-cat active mice, immunohistology revealed increased levels of ␤-catenin in the cytoplasm of ␤ cells, with some cells also exhibiting nuclear localization of ␤-catenin (Fig.…”

“…In one study, conditional disruption of pancreatic ␤-catenin expression produced pancreatitis and reduced islet mass, but the mechanism for impaired islet cell proliferation was not identified (11). In other studies, Wnt signaling disruption led to clear changes in exocrine pancreas growth without detectable changes in endocrine cell proliferation (12)(13)(14). Thus, it remains unclear whether Wnt signaling controls islet cell growth.…”

Pancreas organogenesis: From bud to plexus to gland

“…Acinar differentiation fails early on in the absence of b-catenin (Murtaugh et al, 2005;Dessimoz et al, 2005;Wells et al, 2007). Conversely, pancreas-specific deletion of adenomatous polyposis coli function (APC, endogenous b-catenin inhibitor) (Strom et al, 2007) or b-catenin stabilization (Heiser et al, 2006) at the onset of acinar differentiation results in their massive proliferation, generating an exocrine pancreas twice the normal size. Wnt/b-catenin roles in acinar development may, in part, be mediated by a key downstream target, Myc, whose deletion also impairs acinar formation and proliferation (Nakhai et al, 2008b).…”

“…Wnt/b-catenin roles in acinar development may, in part, be mediated by a key downstream target, Myc, whose deletion also impairs acinar formation and proliferation (Nakhai et al, 2008b). Although early suppression of canonical Wnt signaling is required for proper expansion of pancreatic progenitor numbers, later activation of Wnt signaling in the acinar compartment is required for acinar formation and proliferation (Heiser et al, 2006). It would be interesting to examine the interaction and possible epistatic relationship between Wnt/b-catenin/Myc and Mist1 in controlling acinar cell proliferation.…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…In this regard, it appears that a full complement of Pdx1 is necessary to promote the dissociation of β catenin from its membranous E cadherin anchor, thereby allowing the cytoplasmic and nuclear translocation of β catenin [88]. Precisely how Pdx1 action impinges upon β catenin release is unclear; nonetheless, this pathway may not represent an exclusive mechanism of Pdx1-mediated proliferation, as overexpression of active β catenin alone in late pancreas development appears to have minimal, if any, effects on β cell proliferation ( [90]). These latter data suggest that the confluence of pathways (IR/IRS and β catenin signaling) in the setting of a normal Pdx1 complement is necessary for adaptive β cell proliferation.…”