Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation

Heller, R. Scott; Dichmann, Darwin S.; Jensen, Jan; Miller, Chris R.; Wong, Gordon G.; Madsen, Ole; Serup, Palle

doi:10.1002/dvdy.10157

Cited by 156 publications

(152 citation statements)

References 55 publications

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“…To test whether Wnt signaling controls islet ␤ cell growth, we exposed isolated pancreatic islets to purified Wnt3a, a Wnt family member that is expressed in the developing pancreas and in adult human islets (15). In prior studies we showed that purified Wnt3a led to ␤-catenin stabilization and induction of established Wnt target genes (16).…”

Section: Resultsmentioning

confidence: 99%

Wnt signaling regulates pancreatic β cell proliferation

Rulifson

Karnik

Heiser

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

325

279

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There is widespread interest in defining factors and mechanisms that stimulate proliferation of pancreatic islet cells. Wnt signaling is an important regulator of organ growth and cell fates, and genes encoding Wnt-signaling factors are expressed in the pancreas. However, it is unclear whether Wnt signaling regulates pancreatic islet proliferation and differentiation. Here we provide evidence that Wnt signaling stimulates islet ␤ cell proliferation. The addition of purified Wnt3a protein to cultured ␤ cells or islets promoted expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of ␤ cell cycle progression, and led to increased ␤ cell proliferation in vitro. Conditional pancreatic ␤ cell expression of activated ␤-catenin, a crucial Wnt signal transduction protein, produced similar phenotypes in vivo, leading to ␤ cell expansion, increased insulin production and serum levels, and enhanced glucose handling. Conditional ␤ cell expression of Axin, a potent negative regulator of Wnt signaling, led to reduced Pitx2 and Cyclin D2 expression by ␤ cells, resulting in reduced neonatal ␤ cell expansion and mass and impaired glucose tolerance. Thus, Wnt signaling is both necessary and sufficient for islet ␤ cell proliferation, and our study provides previously unrecognized evidence of a mechanism governing endocrine pancreas growth and function.Cyclin D2 ͉ diabetes mellitus ͉ islets of Langerhans ͉ pancreas ͉ Pitx2

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Section: Resultsmentioning

confidence: 99%

Wnt signaling regulates pancreatic β cell proliferation

Rulifson

Karnik

Heiser

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

325

279

View full text Add to dashboard Cite

show abstract

“…In addition, Wnt signalling molecules and Frizzled receptors are expressed in the endocrine pancreas of both mice and humans [12,16,33] and regulate insulin secretion [17] and beta cell proliferation [19]. In contrast, the canonical Wnt signalling pathway cannot be activated in glucagon-producing alpha cells [34,35].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2007

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Aims/hypothesis Adipocytes secrete signalling molecules that elicit responses from target cells, including pancreatic beta cells. Wnt signalling molecules have recently been identified as novel adipocyte-derived factors. They also regulate insulin secretion in pancreatic beta cells and the cell cycle. The aim of this study was to investigate the effect of adipocyte-derived Wnt signalling molecules on insulin secretion and beta cell proliferation. Methods Human adipocytes were isolated to generate fat cell-conditioned medium (FCCM). Ins-1 cells were stimulated with FCCM and transiently transfected with reporter genes. Proliferation assays using [ 3 H]thymidine incorporation were carried out in Ins-1 cells and primary islet cells. Insulin secretion from primary islets was assessed by radioimmunoassay. Gene expression in primary islets was assessed by Taqman PCR. Results Treatment with human FCCM increased the transcription of a T cell-specific transcription factor reporter gene (TOPFLASH) in Ins-1 cells (241%, p<0.05). FCCM induced the proliferation of Ins-1 cells (1.8 fold, p<0.05) and primary mouse islet cells (1.6 fold, p<0.05). Antagonizing Wnt signalling with secreted Frizzled-related protein 1 (FRP-1) inhibited the proliferative effect induced by Wnt3a and FCCM on Ins-1 cells by 49 and 41%, respectively. In addition, FCCM led to a twofold (p<0.05) induction of cyclin D1 promoter activity in Ins-1 cells. Furthermore, FCCM stimulated insulin secretion (204% of controls, p>0.05) in primary mouse islets, and this stimulation was inhibited by sFRP-1. At a molecular level, canonical Wnt signalling induced glucokinase gene transcription in a peroxisome proliferator-activated receptor γ-dependent fashion, thereby defining the glucokinase gene as a novel Wnt target gene. Conclusions/interpretation Taken together, these data show that adipocyte-derived Wnt signalling molecules induce beta cell proliferation and insulin secretion in vitro, suggesting a novel mechanism linking obesity to hyperinsulinaemia.

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“…At this early stage, FGF10 treatment of dorsal pancreatic endoderm explants was sufficient to increase the expression of Ptf1a, a transcription factor needed to complete pancreatic specification (36,37). Thus, one possibility is that early FGF10 misexpression in the pancreas modifies the pancreatic cell-differentiation program, a mechanism recently suggested to explain the pancreatic phenotype of mice that overexpress Wnt1 under the control of the Pdx1 promoter (38). These mice have pancreatic agenesis.…”

Section: Discussionmentioning

confidence: 97%

Control of β-Cell Differentiation by the Pancreatic Mesenchyme

et al. 2007

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The importance of mesenchymal-epithelial interactions for normal development of the pancreas was recognized in the early 1960s, and mesenchymal signals have been shown to control the proliferation of early pancreatic progenitor cells. The mechanisms by which the mesenchyme coordinates cell proliferation and differentiation to produce the normal number of differentiated pancreatic cells are not fully understood. Here, we demonstrate that the mesenchyme positively controls the final number of ␤-cells that develop from early pancreatic progenitor cells. In vitro, the number of ␤-cells that developed from rat embryonic pancreatic epithelia was larger in cultures with mesenchyme than without mesenchyme. The effect of mesenchyme was not due to an increase in ␤-cell proliferation but was due to increased proliferation of early pancreatic duodenal homeobox-1 (PDX1)-positive progenitor cells, as confirmed by bromodeoxyuridine incorporation. Consequently, the window during which early PDX1؉ pancreatic progenitor cells differentiated into endocrine progenitor cells expressing Ngn3 was extended. Fibroblast growth factor 10 mimicked mesenchyme effects on proliferation of early PDX1؉ progenitor cells and induction of Ngn3 expression. Taken together, our results indicate that expansion of early PDX1؉ pancreatic progenitor cells represents a way to increase the final number of ␤-cells developing from early embryonic pancreas. Diabetes 56:1248-1258, 2007 E pithelium-mesenchyme interactions play a crucial role during organogenesis. They are mediated at least in part by soluble factors produced by the mesenchyme and acting on the epithelium (1). Evidence points to a crucial role for epithelialmesenchymal interactions in cell proliferation and differentiation during pancreatic development (2). However, the mechanisms by which the mesenchyme coordinates cell proliferation and differentiation to produce a normal number of differentiated pancreatic cells are not fully understood.The mature pancreas contains endocrine islets composed of cells producing hormones, such as insulin (␤-cells) and glucagon (␣-cells), and exocrine tissue composed of acinar cells producing enzymes (e.g., carboxypeptidase-A) secreted into the intestine. The pancreas originates from the dorsal and ventral regions of the foregut endoderm. Recently, important findings have shed light on the processes controlling pancreatic endocrine cell development. Studies of genetically engineered mice identified a hierarchy of transcription factors regulating pancreas organogenesis and islet-cell differentiation (3-5). The endodermal region committed to a pancreatic fate first expresses transcription factor pancreatic duodenal homeobox-1 (Pdx1). Pdx1 is detected in mouse embryos on embryonic day 8.5 (E8.5) (E9 in rats) in early pancreatic progenitors. During adulthood, Pdx1 expression becomes largely confined to ␤-cells, where it activates insulin gene transcription (6). Disruption of the Pdx1 gene in mice or human leads to pancreatic agenesis (7,8). These data indicate that P...

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Expression patterns of Wnts, Frizzleds, sFRPs, and misexpression in transgenic mice suggesting a role for Wnts in pancreas and foregut pattern formation

Cited by 156 publications

References 55 publications

Wnt signaling regulates pancreatic β cell proliferation

Wnt signaling regulates pancreatic β cell proliferation

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

Control of β-Cell Differentiation by the Pancreatic Mesenchyme

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