[show abstract][hide abstract] ABSTRACT: Loss of the nuclear hormone receptor hepatocyte nuclear factor 4alpha (HNF4alpha) in hepatocytes results in a complex pleiotropic phenotype that includes a block in hepatocyte differentiation and a severe disruption to liver function. Recent analyses have shown that hepatic gene expression is severely affected by the absence of HNF4alpha, with expression of 567 genes reduced by > or =2.5-fold (P < or = 0.05) in Hnf4alpha(-/-) fetal livers. Although many of these genes are direct targets, HNF4alpha has also been shown to regulate expression of other liver transcription factors, and this raises the possibility that the dependence on HNF4alpha for normal expression of some genes may be indirect. We postulated that the identification of transcription factors whose expression is regulated by HNF4alpha might reveal roles for HNF4alpha in controlling hepatic functions that were not previously appreciated. Here we identify cyclic adenosine monophosphate responsive element binding protein H (CrebH) as a transcription factor whose messenger RNA can be identified in both the embryonic mouse liver and adult mouse liver and whose expression is dependent on HNF4alpha. Analyses of genomic DNA revealed an HNF4alpha binding site upstream of the CrebH coding sequence that was occupied by HNF4alpha in fetal livers and facilitated transcriptional activation of a reporter gene in transient transfection analyses. Although CrebH is highly expressed during hepatogenesis, CrebH(-/-) mice were viable and healthy and displayed no overt defects in liver formation. However, upon treatment with tunicamycin, which induces an endoplasmic reticulum (ER)-stress response, CrebH(-/-) mice displayed reduced expression of acute phase response proteins. CONCLUSION: These data implicate HNF4alpha in having a role in controlling the acute phase response of the liver induced by ER stress by regulating expression of CrebH.
[show abstract][hide abstract] ABSTRACT: Several lines of evidence suggest that GATA6 has an integral role in controlling development of the mammalian liver. Unfortunately, this proposal has been impossible to address directly because mouse embryos lacking GATA6 die during gastrulation. Here we show that the early embryonic deficiency associated with GATA6-knockout mice can be overcome by providing GATA6-null embryos with a wild-type extraembryonic endoderm with the use of tetraploid embryo complementation. Analysis of rescued Gata6-/- embryos revealed that, although hepatic specification occurs normally, the specified cells fail to differentiate and the liver bud does not expand. Although GATA6 is expressed in multiple tissues that impact development of the liver, including the heart, septum transversum mesenchyme, and vasculature, all are relatively unaffected by loss of GATA6, which is consistent with a cell-autonomous requirement for GATA6 during hepatogenesis. We also demonstrate that a closely related GATA factor, GATA4, is expressed transiently in the prehepatic endoderm during hepatic specification and then lost during expansion of the hepatic primordium. Our data support the proposal that GATA4 and GATA6 are functionally redundant during hepatic specification but that GATA6 alone is available for liver bud growth and commitment of the endoderm to a hepatic cell fate.
Molecular and Cellular Biology 05/2005; 25(7):2622-31. · 5.37 Impact Factor