Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function.
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 dominant-negative 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 beta-cell function.
Papadopoulou
Stella
S
Umeå Centre for Molecular Medicine, University of Umeå, S-901 87 Umeå, Sweden.
Edlund
Helena
H
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002455:Cell Division; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology; D051157:Frizzled Receptors / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D005838:Genotype; D005947:Glucose / Q000494:pharmacology; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010179:Pancreas / Q000737:chemistry / Q000196:embryology* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics; D015398:Signal Transduction; D051153:Wnt Proteins / Q000032:analysis / Q000235:genetics; D060528:Wnt4 Protein
D001786:Blood Glucose; D051157:Frizzled Receptors; C486339:Fzd3 protein, mouse; D006023:Glycoproteins; D007328:Insulin; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C095937:Wnt7b protein, mouse; D005947:Glucose