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Background  GATA4 and FOG2 proteins are required for normal cardiac development in mice. It has been proposed that GATA4/FOG2 transcription complex exercises its function through gene activation as well as repression; however, targets of GATA4/FOG2 action in the heart remain elusive.    Results  Here we report identification of the  Lhx9  gene as a direct target of the GATA4/FOG2 complex. We demonstrate that the developing mouse heart normally expresses truncated isoforms of  Lhx9  –  Lhx9α  and  Lhx9β , and not the  Lhx9-HD  isoform that encodes a protein with an intact homeodomain. At E9.5  Lhx9α/β  expression is prominent in the epicardial primordium, septum transversum while  Lhx9-HD  is absent from this tissue; in the E11.5 heart LHX9α/β-positive cells are restricted to the epicardial mesothelium. Thereafter in the control hearts  Lhx9α/β  epicardial expression is promptly down-regulated; in contrast, mouse mutants with  Fog2  gene loss fail to repress  Lhx9α/β  expression. Chromatin immunoprecipitation from the E11.5 hearts demonstrated that  Lhx9  is a direct target for GATA4 and FOG2. In transient transfection studies the expression driven by the cis-regulatory regions of  Lhx9  was repressed by FOG2 in the presence of intact GATA4, but not the GATA4 ki  mutant that is impaired in its ability to bind FOG2.    Conclusion  In summary, the  Lhx9  gene represents the first direct target of the GATA4/FOG2 repressor complex in cardiac development.

GATA4/FOG2 transcriptional complex regulates Lhx9 gene expression in murine heart development