β-Catenin is essential for pancreatic acinar but not islet development

Abstract

Despite our increasingly sophisticated understanding of transcriptional regulation in pancreas development, we know relatively little about the extrinsic signaling pathways involved in this process. We show here that the early pancreatic epithelium exhibits a specific enrichment in unphosphorylatedβ-catenin protein, a hallmark of activation of the canonical Wnt signaling pathway. To determine if this pathway is functionally required for normal pancreas development, we have specifically deleted the β-catenin gene in these cells. Pancreata developing without β-catenin are hypoplastic, although their early progenitors appear normal and exhibit no premature differentiation or death. Surprisingly, and in marked contrast to its role in the intestine, loss of β-catenin does not significantly perturb islet endocrine cell mass or function. The major defect of theβ-catenin-deficient pancreas is an almost complete lack of acinar cells,which normally comprise the majority of the organ. β-Catenin appears to be cell-autonomously required for the specification of acinar cells, rather than for their survival or maintenance, as deletion of β-catenin specifically in differentiated acinar cells has no effect. Thus, our data are consistent with a crucial role for canonical Wnt signals in acinar lineage specification and differentiation.

Control of β-Cell Differentiation by the Pancreatic Mesenchyme

“…These mice have pancreatic agenesis. Comparisons of their phenotype with that of mice deficient in ␤-catenin suggest that Wnt1 overexpression at early development stages may reflect alternative roles for Wnt signaling, such as specifying the fate of the intestine (39). Difference in the stage of development of the explants could also explain the differences between our study and the one by Miralles et al (35).…”

Wnt signaling regulates pancreatic β cell proliferation

“…Thus, the range of nonendocrine and endocrine pancreatic phenotypes reported by us and others (11)(12)(13)(14) likely reflects the distinct experimental strategies and transgenic strains used to disrupt in vivo pancreatic Wnt signaling in these studies.…”

“…This finding suggests that Wnt signaling may be required to maintain islet functions in physiologic conditions demanding adaptive ␤ cell responses. Multiple Wnt ligands, receptors, and signal transduction factors are expressed in the embryonic and adult pancreas (12,13,33), and it is unclear which endogenous factors might mediate Wnt signaling in ␤ cell proliferation. Further studies to clarify these issues may prove useful for generating methods to control pancreatic islet cell proliferation and to test whether Wnt signaling dysregulation might underlie some forms of neuroendocrine tumor pathogenesis.…”

“…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.…”