Development of the mammalian liver and ventral pancreas is dependent on GATA4

BACKGROUND: In the mouse, the parenchyma of both the liver and ventral pancreas is specified from adjacent domains of the ventral foregut endoderm. GATA4, a zinc finger transcription factor, is strongly expressed in these endodermal domains and molecular analyses have implicated GATA4 in potentiating liver gene expression during the onset of hepatogenesis. We therefore hypothesized that GATA4 has an integral role in controlling the early stages of pancreatic and liver development. RESULTS: To determine whether GATA4 contributes to development of either the pancreas or liver we characterized the formation of pancreatic and hepatic tissues in embryos derived from Gata4(-/- )ES cells by tetraploid embryo complementation. In the absence of GATA4, development of the liver and ventral pancreas was disrupted. At embryonic day (E) 9.5, the liver bud failed to expand although, contrary to expectations, the hepatic endoderm was able to form a pseudo-stratified epithelial liver bud that expressed hepatic genes. Moreover, as we had shown previously, the embryos lacked septum transversum mesenchyme suggesting that liver defects may be cell non-autonomous. Analyses of pancreatic development revealed a complete absence of the ventral but not the dorsal pancreas in Gata4(-/- )embryos. Moreover, Gata6(-/- )embryos displayed a similar, although less dramatic phenotype, suggesting a critical role for multiple GATA factors at the earliest stages of ventral pancreas development. CONCLUSION: This study defines integral roles for GATA factors in controlling early development of the mammalian liver and pancreas.