title: Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas.
abstract: Transcriptional and signaling networks establish complex cross-regulatory interactions that drive cellular differentiation during development. Using microarrays we identified the gene encoding the ligand Wnt9a as a candidate target of Neurogenin3, a basic helix-loop-helix transcription factor that functions as a master regulator of pancreatic endocrine differentiation. Here we show that Wnt9a is expressed in the embryonic pancreas and that its deficiency enhances activation of the endocrine transcriptional program and increases the number of endocrine cells at birth. We identify the gene encoding the endocrine transcription factor Nkx2-2 as one of the most upregulated genes in Wnt9a-ablated pancreases and associate its activation to reduced expression of the Wnt effector Tcf7l2. Accordingly, in vitro studies confirm that Tcf7l2 represses activation of Nkx2-2 by Neurogenin3 and inhibits Nkx2-2 expression in differentiated β-cells. Further, we report that Tcf7l2 protein levels decline upon initiation of endocrine differentiation in vivo, disclosing the downregulation of this factor in the developing endocrine compartment. These findings highlight the notion that modulation of signalling cues by lineage-promoting factors is pivotal for controlling differentiation programs.
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Pujadas
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Cervantes
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Tutusaus
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Ejarque
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Sanchez
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: García
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: Y
authors.initials: Y
authors.lastname: Esteban
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Facultat de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Fargas
authors.affiliation: Departament de Ciències Experimentals i de la Salut, Facultat de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Alsina
authors.affiliation: Dept. of Bone and Skeletal Research, Institute of Experimental Musculoskeletal Medicine (IEMM), University Hospital Muenster, Muenster, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Gomis
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomèdiques August Pi i Sunyer, Barcelona, Spain.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Gasa
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002452:Cell Count; D055098:Endocrine Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D010179:Pancreas / Q000033:anatomy & histology / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D051153:Wnt Proteins / Q000172:deficiency*; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C407737:Neurog3 protein, mouse; C000715627:Nkx2-2 protein, mouse; C486388:Wnt9a protein, mouse; C000715630:nkx2.2b protein, zebrafish