title: COUP-TFII controls mouse pancreatic β-cell mass through GLP-1-β-catenin signaling pathways.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute national del santé et de la recherché medicale, Department of Endocrinology, Metabolism and Cancer, Cochin Institute, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutant
authors.forename: Oscar Henrique Pereira
authors.initials: OH
authors.lastname: Ramos
authors.forename: Cécile
authors.initials: C
authors.lastname: Tourrel-Cuzin
authors.forename: Jamileh
authors.initials: J
authors.lastname: Movassat
authors.forename: Anissa
authors.initials: A
authors.lastname: Ilias
authors.forename: David
authors.initials: D
authors.lastname: Vallois
authors.forename: Julien
authors.initials: J
authors.lastname: Planchais
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pégorier
authors.forename: Frans
authors.initials: F
authors.lastname: Schuit
authors.forename: Patrice X
authors.initials: PX
authors.lastname: Petit
authors.forename: Pascale
authors.initials: P
authors.lastname: Bossard
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maedler
authors.forename: Anne
authors.initials: A
authors.lastname: Grapin-Botton
authors.forename: Mireille
authors.initials: M
authors.lastname: Vasseur-Cognet
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051837:COUP Transcription Factor II / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002452:Cell Count; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D010179:Pancreas / Q000187:drug effects / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D051837:COUP Transcription Factor II; C497587:Nr2f2 protein, mouse; D051176:beta Catenin; D052216:Glucagon-Like Peptide 1