Abstract
BackgroundIn 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.ResultsTo 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.ConclusionThis study defines integral roles for GATA factors in controlling early development of the mammalian liver and pancreas.
Highlights
In the mouse, the parenchyma of both the liver and ventral pancreas is specified from adjacent domains of the ventral foregut endoderm
GATA4 is necessary for expansion of the liver bud We have previously shown that producing embryos from ES cells by tetraploid embryo complementation rescues the extra-embryonic defects associated with GATA4 knockout embryos [31]
Because studies of the Alb1 enhancer implicate a role for GATA4 in the potentiation of hepatic gene expression [23], we examined the expression of a number of hepatoblast-expressed genes in these Gata4 null liver buds
Summary
The parenchyma of both the liver and ventral pancreas is specified from adjacent domains of the ventral foregut endoderm. The ventral foregut endoderm differentiates to form the parenchymal components of the liver and ventral pancreas This process begins at approximately embryonic day (E) 8.0 with the ventral foregut positioned such that a portion of it lies immediately adjacent to the cardiac mesoderm with the most ventral region distal from the heart [1,2]. Growth factor signalling from the cardiac mesoderm and septum transversum mesenchyme specifies the underlying endoderm to adopt a hepatic fate such that by the 6–7 somite stage hepatic gene expression can be detected in the ventral foregut endoderm [3,4,5] Concurrent with these events, the most distal region of the foregut endoderm starts to express pancreatic genes [1]. Closure of the foregut pocket positions the newly specified hepatic and ventral pancreatic endoderm in close apposition to inductive mesenchyme that subsequently drives the proliferation and expansion of these organs from approximately E9.0 (reviewed in [7,8])
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