Attenuated Wnt Signaling Perturbs Pancreatic Growth but Not Pancreatic Function

Abstract

Mesenchymal-epithelial interactions are pivotal for proper pancreatic growth and development. We have earlier shown that the fibroblast growth factor (FGF) receptor 2 is expressed in pancreatic progenitor cells and that FGF10, the high-affinity ligand of the FGF receptor 2 isoform FGF receptor 2b, promotes expansion of pancreatic progenitors. The Wnt family of ligands, which signal to the Frizzled (Frz) type receptors, have also been shown to mediate mesenchymal-epithelial interactions and cell proliferation in a variety of different systems. Here, we show that Frz3, like FGF receptor 2, is expressed in the pancreatic epithelium during the proliferative phase of the embryonic pancreas in mice and that overexpression of a dominantnegative form of mouse Frz8 in pancreatic progenitors severely perturbs pancreatic growth. Nevertheless, the transgenic mice remain normoglycemic and display normal glucose tolerance and glucose-stimulated insulin secretion when challenged with exogenous glucose. The maintenance of normoglycemia in these mice appears to be the consequence of a relative increase in endocrine cell number per pancreatic area combined with enhanced insulin biosynthesis and insulin secretion. Collectively, our data provide evidence that Wnt signaling is required for pancreatic growth but not adult ␤-cell function. Diabetes 54: 2844 -2851, 2005 T he embryonic pancreas in mammals forms from a dorsal and ventral protrusion of the primitive gut epithelium (1). These buds grow, branch, and fuse to form the definitive pancreas, a process dependent on mesenchymal-epithelial interactions. Fibroblast growth factor (FGF) signaling has been implicated in the development of many organs that are dependent on mesenchymal-epithelial interactions, including the pancreas (2,3), and several independent studies have demonstrated that FGF signaling is critical for pancreatic growth. FGF ligands have been shown to have a stimulatory effect on pancreatic epithelial cell proliferation in vitro (4), and mice homozygous for a targeted deletion of the Fgf10 gene present with a hypoplastic pancreas due to impaired proliferation of pancreatic epithelial progenitors (5). In contrast, mice overexpressing Fgf10 under the Ipf1/Pdx1 promoter showed enhanced and persistent proliferation of pancreatic progenitors at the expense of pancreatic cell differentiation (6,7).Other factors that stimulate mesenchymal-epithelial interactions are the Wnt family of secreted glycoproteins. Wnts are expressed in a wide variety of mesenchymal tissues and have been shown to stimulate growth of several organs by signaling to epithelial cells (8). They bind to and activate members of the Frizzled (Frz) family of serpetine receptor proteins and are implicated in a variety of developmental processes such as cell differentiation, cell polarity, cell migration, and cell proliferation (9 -12). Several independent studies have demonstrated a key role for Wnt signaling in cell proliferation. During development, Wnt signaling is required in the entire nervous system fo...

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

“…In addition to these known adipocytokines, Wnt signalling molecules are secreted by adipocytes [9,12]. In line with our current study, there is evidence that the Wnt signalling pathway regulates glucose sensing in pancreatic beta cells [17] and prenatal and postnatal beta cell development in mice [18,19]. Beta cell number is determined by their replication, neogenesis and apoptosis [5].…”

“…However, the mechanisms through which TCF7L2 affects glucose metabolism are not clear [14,15]. Frizzled receptors and LRP coreceptors are expressed in pancreatic beta cells [16][17][18].…”

“…Wnts induce cell proliferation in a variety of tissues, including embryonic pancreatic endocrine cells [18]. In addition, genetic ablation of Lrp5 causes impaired insulin secretion in mice, and this occurs in concert with decreased expression of the genes for glucokinase and HNF transcription factors, which regulate glucose sensing in beta cells.…”

Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat

“…Finally, we provide evidence of the modulation of Sfrp5 expression and beta cell proliferation through IGFBP3 availability. There is strong evidence that the Wnt signalling pathway regulates prenatal and postnatal beta cell development in mice as well as glucose sensing in pancreatic beta cells [27,28]. Also, the activation of Wnt signalling in beta cell lines or in isolated islets has been shown to enhance beta cell proliferation [10,[29][30][31].…”

Wnt signaling regulates pancreatic β cell proliferation

“…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.…”