COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways.
<h4>Background</h4>The control of the functional pancreatic β-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how β-cell mass is determined.<h4>Methodology/principal fi...
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oai:doaj.org-article:1f6708c21d4c4516b38f7168046242842021-11-18T07:29:25ZCOUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways.1932-620310.1371/journal.pone.0030847https://doaj.org/article/1f6708c21d4c4516b38f7168046242842012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22292058/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The control of the functional pancreatic β-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how β-cell mass is determined.<h4>Methodology/principal findings</h4>Conditional chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-deficient mice were generated and crossed with mice expressing Cre under the control of pancreatic duodenal homeobox 1 (pdx1) gene promoter. Ablation of COUP-TFII in pancreas resulted in glucose intolerance. Beta-cell number was reduced at 1 day and 3 weeks postnatal. Together with a reduced number of insulin-containing cells in the ductal epithelium and normal β-cell proliferation and apoptosis, this suggests decreased β-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the β-catenin gene and its target genes such as cyclin D1 and axin 2. Moreover, induction of these genes by glucagon-like peptide 1 (GLP-1) via β-catenin was impaired in absence of COUP-TFII. The expression of two other target genes of GLP-1 signaling, GLP-1R and PDX-1 was significantly lower in mutant islets compared to control islets, possibly contributing to reduced β-cell mass. Finally, we demonstrated that COUP-TFII expression was activated by the Wnt signaling-associated transcription factor TCF7L2 (T-cell factor 7-like 2) in human islets and rat β-cells providing a feedback loop.<h4>Conclusions/significance</h4>Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases β-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the β-catenin-dependent pathway and its expression is under the control of TCF7L2.Marie BoutantOscar Henrique Pereira RamosCécile Tourrel-CuzinJamileh MovassatAnissa IliasDavid ValloisJulien PlanchaisJean-Paul PégorierFrans SchuitPatrice X PetitPascale BossardKathrin MaedlerAnne Grapin-BottonMireille Vasseur-CognetPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 1, p e30847 (2012) |
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Medicine R Science Q Marie Boutant Oscar Henrique Pereira Ramos Cécile Tourrel-Cuzin Jamileh Movassat Anissa Ilias David Vallois Julien Planchais Jean-Paul Pégorier Frans Schuit Patrice X Petit Pascale Bossard Kathrin Maedler Anne Grapin-Botton Mireille Vasseur-Cognet COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. |
| description |
<h4>Background</h4>The control of the functional pancreatic β-cell mass serves the key homeostatic function of releasing the right amount of insulin to keep blood sugar in the normal range. It is not fully understood though how β-cell mass is determined.<h4>Methodology/principal findings</h4>Conditional chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-deficient mice were generated and crossed with mice expressing Cre under the control of pancreatic duodenal homeobox 1 (pdx1) gene promoter. Ablation of COUP-TFII in pancreas resulted in glucose intolerance. Beta-cell number was reduced at 1 day and 3 weeks postnatal. Together with a reduced number of insulin-containing cells in the ductal epithelium and normal β-cell proliferation and apoptosis, this suggests decreased β-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured β-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the β-catenin gene and its target genes such as cyclin D1 and axin 2. Moreover, induction of these genes by glucagon-like peptide 1 (GLP-1) via β-catenin was impaired in absence of COUP-TFII. The expression of two other target genes of GLP-1 signaling, GLP-1R and PDX-1 was significantly lower in mutant islets compared to control islets, possibly contributing to reduced β-cell mass. Finally, we demonstrated that COUP-TFII expression was activated by the Wnt signaling-associated transcription factor TCF7L2 (T-cell factor 7-like 2) in human islets and rat β-cells providing a feedback loop.<h4>Conclusions/significance</h4>Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases β-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the β-catenin-dependent pathway and its expression is under the control of TCF7L2. |
| format |
article |
| author |
Marie Boutant Oscar Henrique Pereira Ramos Cécile Tourrel-Cuzin Jamileh Movassat Anissa Ilias David Vallois Julien Planchais Jean-Paul Pégorier Frans Schuit Patrice X Petit Pascale Bossard Kathrin Maedler Anne Grapin-Botton Mireille Vasseur-Cognet |
| author_facet |
Marie Boutant Oscar Henrique Pereira Ramos Cécile Tourrel-Cuzin Jamileh Movassat Anissa Ilias David Vallois Julien Planchais Jean-Paul Pégorier Frans Schuit Patrice X Petit Pascale Bossard Kathrin Maedler Anne Grapin-Botton Mireille Vasseur-Cognet |
| author_sort |
Marie Boutant |
| title |
COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. |
| title_short |
COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. |
| title_full |
COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. |
| title_fullStr |
COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. |
| title_full_unstemmed |
COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways. |
| title_sort |
coup-tfii controls mouse pancreatic β-cell mass through glp-1-β-catenin signaling pathways. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/1f6708c21d4c4516b38f716804624284 |
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