| First Author | Boutant M | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 1 | Pages | e30847 |
| PubMed ID | 22292058 | Mgi Jnum | J:184224 |
| Mgi Id | MGI:5320521 | Doi | 10.1371/journal.pone.0030847 |
| Citation | Boutant M, et al. (2012) COUP-TFII controls mouse pancreatic beta-cell mass through GLP-1-beta-catenin signaling pathways. PLoS One 7(1):e30847 |
| abstractText | BACKGROUND: The control of the functional pancreatic beta-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 beta-cell mass is determined. METHODOLOGY/PRINCIPAL FINDINGS: 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 beta-cell proliferation and apoptosis, this suggests decreased beta-cell differentiation in the neonatal period. By testing islets isolated from these mice and cultured beta-cells with loss and gain of COUP-TFII function, we found that COUP-TFII induces the expression of the beta-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 beta-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 beta-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 beta-cells providing a feedback loop. CONCLUSIONS/SIGNIFICANCE: Our findings show that COUP-TFII is a novel component of the GLP-1 signaling cascade that increases beta-cell number during the neonatal period. COUP-TFII is required for GLP-1 activation of the beta-catenin-dependent pathway and its expression is under the control of TCF7L2. |
