Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1

Notch signaling through the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are less well defined. Furthermore, whether Notch signaling also underlies adult hepatic cell fate decisions is largely unknown. By implementing different genetic mouse models, we provide a comprehensive analysis that defines the role of Notch in cell fate control in the developing and adult liver. We show that cell-specific activation of Notch2 signaling by a Notch2IC (N2IC) transgene leads to rapid biliary specification of embryonic hepatoblasts, but also-when expressed in up to 6-month-old adult livers-rapidly reprograms adult hepatocytes to biliary cells with formation of tubular-cystic structures. When directed specifically to the adult biliary and facultative liver progenitor cell compartment, Notch2 is capable of inducing a ductular reaction. Furthermore, we characterized the significance of key effectors of canonical Notch signaling during normal development and in N2IC-expressing models. We demonstrate that tubule formation of intrahepatic bile ducts during embryonic development as well as N2IC-induced specification and morphogenesis of embryonic hepatoblasts and biliary conversion of adult hepatocytes all critically rely on canonical Notch signaling via recombination signal binding protein (RBP)-Jκ but do not require Hes1. Conclusion: Notch2 appears to be the main determinant not only of biliary commitment of embryonic hepatoblasts during development but also of biliary reprogramming of adult hepatocytes. Notch2-dictated cell fates and morphogenesis in both embryonic hepatoblasts and adult hepatocytes rely on canonical Notch signaling but do not require Hes1. Adult liver cells possess a remarkable plasticity to assume new cell fates when embryonic signaling pathways are active.