title: GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice.
abstract: The zinc finger transcription factor GATA4 controls specification and differentiation of multiple cell types during embryonic development. In mouse embryonic liver, Gata4 is expressed in the endodermal hepatic bud and in the adjacent mesenchyme of the septum transversum. Previous studies have shown that Gata4 inactivation impairs liver formation. However, whether these defects are caused by loss of Gata4 in the hepatic endoderm or in the septum transversum mesenchyme remains to be determined. In this study, we have investigated the role of mesenchymal GATA4 activity in liver formation. We have conditionally inactivated Gata4 in the septum transversum mesenchyme and its derivatives by using Cre/loxP technology. We have generated a mouse transgenic Cre line, in which expression of Cre recombinase is controlled by a previously identified distal Gata4 enhancer. Conditional inactivation of Gata4 in hepatic mesenchymal cells led to embryonic lethality around mouse embryonic stage 13.5, likely as a consequence of fetal anemia. Gata4 knockout fetal livers exhibited reduced size, advanced fibrosis, accumulation of extracellular matrix components and hepatic stellate cell (HSC) activation. Haploinsufficiency of Gata4 accelerated CCl4 -induced liver fibrosis in adult mice. Moreover, Gata4 expression was dramatically reduced in advanced hepatic fibrosis and cirrhosis in humans.
  
  
  CONCLUSIONS
  Our data demonstrate that mesenchymal GATA4 activity regulates HSC activation and inhibits the liver fibrogenic process.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Sevilla, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Delgado
authors.forename: Manuel
authors.initials: M
authors.lastname: Carrasco
authors.forename: Elena
authors.initials: E
authors.lastname: Cano
authors.forename: Rita
authors.initials: R
authors.lastname: Carmona
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Carbonero
authors.forename: Luis M
authors.initials: LM
authors.lastname: Marín-Gómez
authors.forename: Bernat
authors.initials: B
authors.lastname: Soria
authors.forename: Francisco
authors.initials: F
authors.lastname: Martín
authors.forename: David A
authors.initials: DA
authors.lastname: Cano
authors.forename: Ramón
authors.initials: R
authors.lastname: Muñoz-Chápuli
authors.forename: Anabel
authors.initials: A
authors.lastname: Rojas
mesh_terms: D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000150:complications; D002460:Cell Line; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000502:physiology; D006801:Humans; D019426:Integrases; D008099:Liver / Q000196:embryology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; C045073:Cre recombinase; D019426:Integrases