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

Abstract

During development, the endoderm initiates organ-restricted gene expression patterns in a spatiotemporally controlled manner. This process, termed induction, requires signals from adjacent mesodermal derivatives. Fibroblast Growth Factor (FGF) and Bone Morphogenetic Protein (BMP) emanating from the cardiac mesoderm and the septum transversum mesenchyme (STM), respectively, are believed to be simultaneously and uniformly required to directly induce hepatic gene expression from the murine endoderm. Using small molecule inhibitors of BMP signals during liver bud induction in the developing mouse embryo, we find that BMP signaling is not uniformly required to induce hepatic gene expression. Although BMP inhibition causes an overall reduction in the number of induced hepatoblasts, the STM-bounded posterior liver bud demonstrates the most severe loss of the essential hepatic transcription factor Hepatocyte nuclear factor 4-α (HNF4α) while the sinus venosus (SV)-lined anterior liver bud is less affected. We find that the posterior liver bud progenitors are anteriorly displaced and aberrantly activate pancreatobiliary markers including SOX9. Additionally, we find that ectopically expressed SOX9 inhibits HNF4α and that BMP is indirectly required for hepatoblast induction. Finally, because previous work demonstrated that FGF signals were essential for anterior but not posterior liver bud induction, we examined synchronous BMP and FGF inhibition and find that this leads to a massive loss of induced hepatoblasts. Conclusions: BMP signaling is required to maintain the hepato-pancreatobiliary boundary, at least in part, by indirectly repressing SOX9 in the hepatic endoderm. BMP and FGF signals are each required for the induction of spatially complementary subsets of hepatoblasts. These results highlight the importance of studying early inductive processes in the whole embryo. This article is protected by copyright. All rights reserved.

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