FGF signaling is required for anterior but not posterior specification of the murine liver bud

Abstract

Background The definitive endoderm arises as a naive epithelial sheet that produces the entire gut tube and associated organs including the liver, pancreas and lungs. Murine explant studies demonstrate that Fibroblast Growth Factor (FGF) signaling from adjacent tissues is required to induce hepatic gene expression from isolated foregut endoderm. The requirement of FGF signaling during liver development is examined via small molecule inhibition during whole embryo culture. Results Loss of FGF signaling prior to hepatic induction results in morphological defects and gene expression changes that are confined to the anterior liver bud. In contrast the posterior portion of the liver bud remains relatively unaffected. Because FGF is thought to act as a morphogen during endoderm organogenesis, the ventral pancreas was also examined after FGF inhibition. Although the size of the ventral pancreas is not affected, loss of FGF signaling results in a significantly higher density of ventral pancreas cells. Conclusions The requirement for FGF-mediated induction of hepatic gene expression differs across the anterior-posterior axis of the developing liver bud. These results underscore the importance of studying tissue differentiation in the context of the whole embryo.

Patterning of the hepato‐pancreatobiliary boundary by BMP reveals heterogeneity within the murine liver bud

“…The first is that the hepatic endoderm induction occurs differentially along the anterior/posterior axis. Posterior hepatoblast induction requires BMP signals, whereas anterior induction requires FGF signals . In agreement with this idea, we have demonstrated that the anterior and posterior hepatic endoderm is adjacent to distinct and potentially inductive mesoderm derivatives.…”

“…We previously demonstrated that small molecule–mediated inhibition of FGF signaling leads to a selective loss of HNF4α in the anterior but not posterior liver bud of cultured embryos . Whereas E9.25 controls displayed pronouncedly thickened liver buds, loss of FGF signaling produced increased cell death throughout the bud and an abnormal thinning and loss of HNF4α in the anterior liver bud .…”

“…We previously demonstrated that small molecule–mediated inhibition of FGF signaling leads to a selective loss of HNF4α in the anterior but not posterior liver bud of cultured embryos . Whereas E9.25 controls displayed pronouncedly thickened liver buds, loss of FGF signaling produced increased cell death throughout the bud and an abnormal thinning and loss of HNF4α in the anterior liver bud . Indeed, after simultaneous exposure to the BMP and FGF inhibitors DMH1 and SU5402, respectively, HNF4α expression is almost completely lost, much of the presumptive liver bud is abnormally thin, and SOX9 ectopically expressed throughout the hepatic domain (Fig.…”

“…Section in situ hybridization was performed as described previously (see also the http://onlinelibrary.wiley.com/doi/10.1002/hep.29769/suppinfo) using antisense probes for Afp and sex‐determining region Y‐box 17 ( Sox17 ) (IMAGE clone: 1529001).…”

At new heights – endodermal lineages in development and disease

“…For example, Kimberly Tremblay (University of Massachusetts, Amherst, USA) showed by fate mapping and laser ablation, that the lateral progenitors form the majority of the liver bud and require vascular endothelial growth factor (VEGF) for survival. By contrast, the medial progenitors contribute to the anterior bud and require fibroblast growth factor (FGF) signaling for specification (Wang et al, 2015b). It is unknown whether the progeny of these distinct progenitor populations produce functionally equivalent hepatic tissue.…”