Cardiac Expression of Tnnt1 Requires the GATA4-FOG2 Transcription Complex

Previous work by us and others has shown that the loss of interaction between GATA4 and FOG2 protein partners is embryonic lethal due to heart failure at embryonic day (E) 13.5; however, the role of this important protein duo in various cardiac compartments (e.g., myocardial, endocardial, or epicardial cells) remains to be understood. Although a dual role (both as an activator and a repressor) for the GATA4-FOG2 transcriptional complex has been put forward, the specific genes under GATA4-FOG2 control in the developing heart have remained largely elusive. Since the myocardial-restricted Fog2 re-expression in the Fog2 null embryos is sufficient to extend their life span, identification of GATA4-FOG2 target genes in cardiomyocytes could shed light on the molecular mechanism of GATA4-FOG2 action in these cells. We report here that cardiac expression of slow skeletal troponin T (Tnnt1) strictly depends on the physical interaction between GATA4-FOG2 in the myocardium of both atria and ventricles

Ovarian Development in Mice Requires the GATA4-FOG2 Transcription Complex

We have demonstrated previously that mammalian sexual differentiation requires both the GATA4 and FOG2 transcriptional regulators to assemble the functioning testis. Here we have determined that the sexual development of female mice is profoundly affected by the loss of GATA4-FOG2 interaction. We have also identified the Dkk1 gene, which encodes a secreted inhibitor of canonical beta-catenin signaling, as a target of GATA4-FOG2 repression in the developing ovary. The tissue-specific ablation of the beta-catenin gene in the gonads disrupts female development. In Gata4(ki/ki); Dkk1(-/-) or Fog2(-/-); Dkk1(-/-) embryos, the normal ovarian gene expression pattern is partially restored. Control of ovarian development by the GATA4-FOG2 complex presents a novel insight into the cross-talk between transcriptional regulation and extracellular signaling that occurs in ovarian development

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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>Here we report identification of the <it>Lhx9 </it>gene as a direct target of the GATA4/FOG2 complex. We demonstrate that the developing mouse heart normally expresses truncated isoforms of <it>Lhx9 </it>– <it>Lhx9α </it>and <it>Lhx9β</it>, and not the <it>Lhx9-HD </it>isoform that encodes a protein with an intact homeodomain. At E9.5 <it>Lhx9α/β </it>expression is prominent in the epicardial primordium, septum transversum while <it>Lhx9-HD </it>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 <it>Lhx9α/β </it>epicardial expression is promptly down-regulated; in contrast, mouse mutants with <it>Fog2 </it>gene loss fail to repress <it>Lhx9α/β </it>expression. Chromatin immunoprecipitation from the E11.5 hearts demonstrated that <it>Lhx9 </it>is a direct target for GATA4 and FOG2. In transient transfection studies the expression driven by the cis-regulatory regions of <it>Lhx9 </it>was repressed by FOG2 in the presence of intact GATA4, but not the GATA4^kimutant that is impaired in its ability to bind FOG2.</p> <p>Conclusion</p> <p>In summary, the <it>Lhx9 </it>gene represents the first direct target of the GATA4/FOG2 repressor complex in cardiac development.</p

Fog2 is required for normal diaphragm and lung development in mice and humans

Congenital diaphragmatic hernia and other congenital diaphragmatic defects are associated with significant mortality and morbidity in neonates; however, the molecular basis of these developmental anomalies is unknown. In an analysis of E18.5 embryos derived from mice treated with N-ethyl-N-nitrosourea, we identified a mutation that causes pulmonary hypoplasia and abnormal diaphragmatic development. Fog2 (Zfpm2) maps within the recombinant interval carrying the N-ethyl-N-nitrosourea-induced mutation, and DNA sequencing of Fog2 identified a mutation in a splice donor site that generates an abnormal transcript encoding a truncated protein. Human autopsy cases with diaphragmatic defect and pulmonary hypoplasia were evaluated for mutations in FOG2. Sequence analysis revealed a de novo mutation resulting in a premature stop codon in a child who died on the first day of life secondary to severe bilateral pulmonary hypoplasia and an abnormally muscularized diaphragm. Using a phenotype-driven approach, we have established that Fog2 is required for normal diaphragm and lung development, a role that has not been previously appreciated. FOG2 is the first gene implicated in the pathogenesis of nonsyndromic human congenital diaphragmatic defects, and its necessity for pulmonary development validates the hypothesis that neonates with congenital diaphragmatic hernia may also have primary pulmonary developmental abnormalities