GATA4 and GATA6 control mouse pancreas organogenesis

Recently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene...

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Autores: Carrasco, Manuel, Delgado, Irene, Soria Escoms, Bernat, Martín, Franz, Rojas, Anabel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2012
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/121662
Acceso en línea:http://hdl.handle.net/10261/121662
Access Level:acceso abierto
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spelling GATA4 and GATA6 control mouse pancreas organogenesisCarrasco, ManuelDelgado, IreneSoria Escoms, BernatMartín, FranzRojas, AnabelRecently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene did not have a major impact on pancreas formation, indicating functional redundancy. However, double Gata4/Gata6 mutant mice failed to develop pancreata, died shortly after birth, and displayed hyperglycemia. Morphological defects in Gata4/Gata6 mutant pancreata were apparent during embryonic development, and the epithelium failed to expand as a result of defects in cell proliferation and differentiation. The number of multipotent pancreatic progenitors, including PDX1 + cells, was reduced in the Gata4/Gata6 mutant pancreatic epithelium. Remarkably, deletion of only 1 Gata6 allele on a Gata4 conditional knockout background severely reduced pancreatic mass. In contrast, a single WT allele of Gata4 in Gata6 conditional knockout mice was sufficient for normal pancreatic development, indicating differential contributions of GATA factors to pancreas formation. Our results place GATA factors at the top of the transcriptional network hierarchy controlling pancreas organogenesis.M. Carrasco was supported by a predoctoral fellowship from the Spanish Ministry of Education. I. Delgado was supported by a contract from Consejería de Salud, Junta de Andalucía (PI-0008). This work was supported by grants from ISCIII cofunded by Fondos FEDER (PI08/0018, PI11/01125 to A. Rojas) (RD06/0010/0025 and PI10/00964 to B. Soria), Consejería de Economía, Innovación y Ciencia (P10.CTS.6505 to B. Soria), and from Consejería de Salud, Junta de Andalucía (PI-0008/2009 to A. Rojas) (PI-022/2008 to F. Martín).Peer ReviewedAmerican Society for Clinical InvestigationMinisterio de Educación (España)Junta de AndalucíaInstituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2015201520122015info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/121662reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1172/JCI63240Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1216622026-05-22T06:33:51Z
dc.title.none.fl_str_mv GATA4 and GATA6 control mouse pancreas organogenesis
title GATA4 and GATA6 control mouse pancreas organogenesis
spellingShingle GATA4 and GATA6 control mouse pancreas organogenesis
Carrasco, Manuel
title_short GATA4 and GATA6 control mouse pancreas organogenesis
title_full GATA4 and GATA6 control mouse pancreas organogenesis
title_fullStr GATA4 and GATA6 control mouse pancreas organogenesis
title_full_unstemmed GATA4 and GATA6 control mouse pancreas organogenesis
title_sort GATA4 and GATA6 control mouse pancreas organogenesis
dc.creator.none.fl_str_mv Carrasco, Manuel
Delgado, Irene
Soria Escoms, Bernat
Martín, Franz
Rojas, Anabel
author Carrasco, Manuel
author_facet Carrasco, Manuel
Delgado, Irene
Soria Escoms, Bernat
Martín, Franz
Rojas, Anabel
author_role author
author2 Delgado, Irene
Soria Escoms, Bernat
Martín, Franz
Rojas, Anabel
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Educación (España)
Junta de Andalucía
Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Recently, heterozygous mutations in GATA6 have been found in neonatal diabetic patients with failed pancreatic organogenesis. To investigate the roles of GATA4 and GATA6 in mouse pancreas organogenesis, we conditionally inactivated these genes within the pancreas. Single inactivation of either gene did not have a major impact on pancreas formation, indicating functional redundancy. However, double Gata4/Gata6 mutant mice failed to develop pancreata, died shortly after birth, and displayed hyperglycemia. Morphological defects in Gata4/Gata6 mutant pancreata were apparent during embryonic development, and the epithelium failed to expand as a result of defects in cell proliferation and differentiation. The number of multipotent pancreatic progenitors, including PDX1 + cells, was reduced in the Gata4/Gata6 mutant pancreatic epithelium. Remarkably, deletion of only 1 Gata6 allele on a Gata4 conditional knockout background severely reduced pancreatic mass. In contrast, a single WT allele of Gata4 in Gata6 conditional knockout mice was sufficient for normal pancreatic development, indicating differential contributions of GATA factors to pancreas formation. Our results place GATA factors at the top of the transcriptional network hierarchy controlling pancreas organogenesis.
publishDate 2012
dc.date.none.fl_str_mv 2012
2015
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/121662
url http://hdl.handle.net/10261/121662
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1172/JCI63240
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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