title: WT1 regulates the expression of inhibitory chemokines during heart development.
abstract: The embryonic epicardium is an important source of cardiovascular precursor cells and paracrine factors that are required for adequate heart formation. Signaling pathways regulated by WT1 that promote heart development have started to be described; however, there is little information on signaling pathways regulated by WT1 that could act in a negative manner. Transcriptome analysis of Wt1KO epicardial cells reveals an unexpected role for WT1 in repressing the expression of interferon-regulated genes that could be involved in a negative regulation of heart morphogenesis. Here, we showed that WT1 is required to repress the expression of the chemokines Ccl5 and Cxcl10 in epicardial cells. We observed an inverse correlation of Wt1 and the expression of Cxcl10 and Ccl5 during epicardium development. Chemokine receptor analyses of hearts from Wt1(gfp/+) mice demonstrate the differential expression of their chemokine receptors in GFP(+) epicardial enriched cells and GFP(-) cells. Functional assays demonstrate that CXCL10 and CCL5 inhibit epicardial cells migration and the proliferation of cardiomyocytes respectively. WT1 regulates the expression levels of Cxcl10 and Ccl5 in epicardial cells directly and indirectly through increasing the levels of IRF7. As epicardial cell reactivation after a myocardial damage is linked with WT1 expression, the present work has potential implications in adult heart repair.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Velecela
authors.forename: Laura A
authors.initials: LA
authors.lastname: Lettice
authors.forename: You-Ying
authors.initials: YY
authors.lastname: Chau
authors.forename: Joan
authors.initials: J
authors.lastname: Slight
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Berry
authors.forename: Anna
authors.initials: A
authors.lastname: Thornburn
authors.forename: Quinn D
authors.initials: QD
authors.lastname: Gunst
authors.forename: Maurice
authors.initials: M
authors.lastname: van den Hoff
authors.forename: Manuel
authors.initials: M
authors.lastname: Reina
authors.forename: Fernando O
authors.initials: FO
authors.lastname: Martínez
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Ofelia M
authors.initials: OM
authors.lastname: Martínez-Estrada
mesh_terms: D000818:Animals; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006321:Heart / Q000254:growth & development*; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010496:Pericardium / Q000166:cytology / Q000254:growth & development*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D019707:Receptors, Chemokine; D025721:WT1 Proteins