Liver and pancreas are derivatives of the endodermal germ layer that become specified around E8.5 in the mouse embryo. The pancreas arises from two distinct regions in the foregut, one dorsally, one ventrally located. Interestingly, the ventral pancreatic domain overlaps with the prospective hepatic endoderm and both organ rudiments develop in close proximity to one another throughout early development. Previous analyses suggested that liver and ventral pancreas arise from a common progenitor domain. However, this hypothesis had not been validated in mammalian embryos in vivo. In addition, the cellular and tissue dynamics defining hepatic and pancreatic lineage segregation from this presumed common progenitor domain remained elusive.
In this study, I applied complementary genetic lineage tracing approaches in mouse models to label early hepato-pancreatic progenitors and to follow their contribution to liver and pancreas in vivo. By employing a combination of unicolor and multicolor (Confetti) reporter systems, I traced the common origin of liver and ventral pancreas to a bipotent progenitor domain situated in the ventral foregut. In addition, I uncovered the surprising fact that ventral pancreatic cells retain the bipotent nature of these ventral foregut progenitors and contribute to the growing liver rudiment throughout early organogenesis. In vivo analyses of marker gene expression suggested that this progenitor population is characterized by the concurrent expression of the transcription factors Prox1, Pdx1, and Sox17. I substantiated these findings of pancreatic cell fate plasticity by detailed in vivo time course analyses of cell numbers and proliferation dynamics in the hepato-pancreatic organ system. Finally, I identified Robo-Slit signaling as an essential signaling pathway to maintain pancreatic identity and to prevent aberrant hepatic fate acquisition within the ventral pancreatic domain.
Taken together, by combining genetic lineage tracing and quantitative immunohistochemical analyses in genetic mouse models in vivo, I uncovered that ventral pancreatic cells display a hitherto unappreciated level of cell fate plasticity fundamental for proper development of ventral foregut derivatives.
