Endothelial lineage-mediated loss of the GATA cofactor Friend of GATA 1 impairs cardiac development.
GATA transcription factors, together with Friend of GATA (FOG) cofactors, are required for the differentiation of diverse cell types. Multiple aspects of hematopoiesis are controlled by the interaction of FOG-1 with the GATA-1/2/3 subfamily. Likewise, FOG-2 is coexpressed with the GATA-4/5/6 subfamily at other sites, including the heart and gonads. FOG-2 and GATA-4 are required for cardiac development. Through transgenic rescue of hematopoietic defects of FOG-1-/- embryos we define an unsuspected role for FOG-1 in heart development. In particular, rescued FOG-1-/- mice die at embryonic day (E) 14.5 with cardiac defects that include double outlet right ventricle and a common atrioventricular valve. Using conditional inactivation of Fog-1 we assign the cell of origin in which FOG-1 function is required. Neural crest cells migrate properly into FOG-1-/- hearts and mice with FOG-1 conditionally excised from neural crest derivatives fail to develop cardiac abnormalities. In contrast, conditional inactivation of FOG-1 in endothelial-derived tissues by means of Tie-2-expressed Cre recapitulates the rescue-knockout defects. These findings establish a nonredundant requirement for FOG-1 in the outlet tract and atrioventricular valves of the heart that depend on expression in endothelial-derived tissue and presumably reflect cooperation with the GATA-4/5/6 subfamily.
Katz
Samuel G
SG
Division of Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Williams
Aimee
A
Yang
Jifu
J
Fujiwara
Yuko
Y
Tsang
Alice P
AP
Epstein
Jonathan A
JA
Orkin
Stuart H
SH
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004727:Endothelium / Q000196:embryology; D050981:Erythroid-Specific DNA-Binding Factors; D005318:Fetal Heart / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D050982:GATA1 Transcription Factor; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009432:Neural Crest / Q000196:embryology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse