Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas

Pujadas, Gemma; Cervantes, Sara; Tutusaus, Anna; Ejarque, Miriam; Sánchez, Lidia; García, Ainhoa; Esteban, Yaiza; Fargas Madriles, Laura, 1989-; Alsina i Español, Berta; Hartmann, Christian; Gomis, Ramon; Gasa, Rosa

Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Pujadas, Gemmaca
dc.contributor.author Cervantes, Saraca
dc.contributor.author Tutusaus, Annaca
dc.contributor.author Ejarque, Miriamca
dc.contributor.author Sánchez, Lidiaca
dc.contributor.author García, Ainhoaca
dc.contributor.author Esteban, Yaizaca
dc.contributor.author Fargas Madriles, Laura, 1989-ca
dc.contributor.author Alsina i Español, Bertaca
dc.contributor.author Hartmann, Christianca
dc.contributor.author Gomis, Ramonca
dc.contributor.author Gasa, Rosaca
dc.date.accessioned 2016-03-29T14:18:27Z
dc.date.available 2016-03-29T14:18:27Z
dc.date.issued 2016
dc.description.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.ca
dc.description.sponsorship This work has been supported by the Spanish Ministerio de Ciencia e Innovación (BFU2008-02299/BMC to RGa), Ministerio de Economía y Competitividad/Instituto de Salud Carlos III (PI13/01500 to RGa) and Generalitat de Catalunya (2014 SGR659 to RGo). Predoctoral fellowships were provided by the Spanish Ministerio de Ciencia e Innovación (BES-2007- 17284, GP) and IDIBAPS (ME). The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2009-2013) under the grant agreement n°229673 (SC). CIBERDEM (Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas) is an initiative of the Instituto de Salud Carlos III.
dc.format.mimetype application/pdfca
dc.identifier.citation Pujadas G, Cervantes S, Tutusaus A, Ejarque M, Sanchez L, García A et al. Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas. Scientific reports. 2016; 6: 19223. DOI 10.1038/srep19223ca
dc.identifier.doi http://dx.doi.org/10.1038/srep19223
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/26030
dc.language.iso engca
dc.publisher Nature Publishing Groupca
dc.relation.ispartof Scientific reports. 2016; 6: 19223
dc.rights © Nature Publishing Group. http://www.nature.com/articles/srep19223/nThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
dc.subject.other Pàncreesca
dc.title Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreasca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

Col·leccions

Articles (Departament de Medicina i Ciències de la Vida)