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FGFs and Wnts in pancreatic growth and β-cell function
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mesenchymal-epithelial interactions are pivotal for proper pancreatic growth and development. The pancreatic progenitor cells present in the early pancreatic anlagen proliferate and eventually give rise to all pancreatic cell types. The Fibroblast Growth Factor 2b (FGFR2b) high-affinity ligand Fibroblast Growth Factor 10 (FGF10) has been linked to pancreatic epithelial cell proliferation and we have previously shown that Notch signalling controls pancreatic cell differentiation via lateral inhibition. By overexpressing FGF10 under the control of the Ipf1/Pdx1 promoter in mice, we have shown that persistent FGF10 activation in the embryonic pancreas of transgenic mice perturbs pancreatic epithelial cell proliferation and also inhibits pancreatic cell differentiation by maintaining Notch activation. In the Ipf1/Fgf10 transgenic mice, the pancreatic epithelial cells are ‘locked’ in an undifferentiated progenitor-like state with sustained proliferative capacity. Collectively, our data suggest a key role for FGFR2b/FGF10 signalling in the regulation of pancreatic growth and differentiation and that FGFR2b/FGF10 signalling interact with the Notch signalling pathway.

Glucose homeostasis in mammals is critically dependent on co-ordinated glucose uptake, oxidative metabolism and insulin secretion in β-cells. Although, several key genes controlling various aspects of glucose sensing, glucose metabolism, insulin expression and secretion have been identified, we know relatively little about the molecular mechanisms that induce and maintain the expression of genes required for glucose-stimulated insulin secretion (GSIS) in β-cells. Attenuation of FGFR1c signalling leads to diabetes in mice. Overexpression of FGF2, a high-affinity FGFR1c ligand, under the control of the Ipf1/Pdx1 promoter also leads to diabetes in mice. The Ipf1/Fgf2 mice present with normal endocrine and exocrine differentiation but display impaired glucose-stimulated insulin secretion (GSIS), perturbed expression of genes required for glucose sensing uptake together with oxidative metabolism and increased expression of the FGF-signalling inhibitors Spry-2 and Pyst1/MKP3 in β-cells. Thus, stringent control of FGF signalling activation appears crucial for the maintenance of the regulatory circuit that ensures proper GSIS in pancreatic β-cells and hence normoglycaemia.

The Wnt family of ligands via their receptors Frizzled (Frz) have been shown to mediate mesenchymal-epithelial interactions and cell proliferation in a variety of different systems. Expression of a plethora of Wnt ligands and Frz receptors has been previously reported in the pancreas and mice missexpressing Wnt1 and Wnt5a under the Ipf1/Pdx1 promoter display severely perturbed development. Here, we show the temporal and spatial expression of Wnt4, Wnt7b and Frz3 at different stages of pancreas development. To elucidate the role of Wnt signalling in the pancreas, we overexpressed a dominant negative form of mouse Frz8 under the Ipf1/Pdx1 promoter in mice. The Ipf1/Frz8CRD mice display severe pancreatic hypoplasia demonstrating that attenuation of Wnt signalling in the pancreas leads to perturbed pancreatic growth. Nevertheless, the transgenic mice present with normal endocrine and exocrine differentiation and remain normoglycaemic. The maintenance of normoglycaemia 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 signalling is required pancreatic growth but not adult β-cell function.

Place, publisher, year, edition, pages
Umeå: Umeå centrum för molekylär medicin (UCMM) , 2005. , 87 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 966
Keyword [en]
Molecular biology, Wnt, FGF, pancreas, Notch, signal transduction, development, proliferation, progenitors, β-cells, feedback, GSIS, diabetes
Keyword [sv]
Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-528ISBN: 91-7305-866-1 (print)OAI: oai:DiVA.org:umu-528DiVA: diva2:143716
Public defence
2005-06-01, 09:00 (English)
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2009-11-26Bibliographically approved
List of papers
1. Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells.
Open this publication in new window or tab >>Fgf10 maintains notch activation, stimulates proliferation, and blocks differentiation of pancreatic epithelial cells.
2003 (English)In: Developmental Dynamics, ISSN 1058-8388, E-ISSN 1097-0177, Vol. 228, no 2, 185-193 p.Article in journal (Refereed) Published
Abstract [en]

The pancreas is an endodermally derived organ that initially appears as a dorsal and ventral protrusion of the primitive gut epithelium. The pancreatic progenitor cells present in these early pancreatic anlagen proliferate and eventually give rise to all pancreatic cell types. The fibroblast growth factor receptor (FGFR) 2b high-affinity ligand FGF10 has been linked to pancreatic epithelial cell proliferation, and we have shown previously that Notch signalling controls pancreatic cell differentiation by means of lateral inhibition. In the developing pancreas, activated intracellular Notch appears to be required for maintaining cells in the progenitor state, in part by blocking the expression of the pro-endocrine gene neurogenin 3 (ngn3), and hence endocrine cell differentiation. Here, we show that persistent expression of Fgf10 in the embryonic pancreas of transgenic mice also inhibits pancreatic cell differentiation, while stimulating pancreatic epithelial cell proliferation. We provide evidence that one of the effects of the persistent expression of Fgf10 in the developing pancreas is maintained Notch activation, which results in impaired expression of ngn3 within the pancreatic epithelium. Together, our data suggest a role for FGF10/FGFR2b signalling in regulation of pancreatic cell proliferation and differentiation and that FGF10/FGFR2b signalling affects the Notch-mediated lateral inhibition pathway.

Identifiers
urn:nbn:se:umu:diva-29897 (URN)10.1002/dvdy.10368 (DOI)14517990 (PubMedID)
Available from: 2009-11-26 Created: 2009-11-26 Last updated: 2017-12-12
2. Persistent FGF signalling in b-cells leads to diabetes in mice
Open this publication in new window or tab >>Persistent FGF signalling in b-cells leads to diabetes in mice
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4563 (URN)
Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2010-01-13Bibliographically approved
3. Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function.
Open this publication in new window or tab >>Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function.
2005 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 54, no 10, 2844-2851 p.Article in journal (Refereed) Published
Abstract [en]

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.

Identifiers
urn:nbn:se:umu:diva-29899 (URN)10.2337/diabetes.54.10.2844 (DOI)16186384 (PubMedID)
Available from: 2009-11-26 Created: 2009-11-26 Last updated: 2017-12-12

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