Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors

Clotman, Frédéric [UCL] Courtoy, Pierre J. [UCL] Jacquemin, Patrick [UCL] Plumb-Rudewiez, Nicolas [UCL] Pierreux, Christophe [UCL] Van Der Smissen, Patrick [UCL] Dietz, Harry C Rousseau, Guy [UCL] Lemaigre, Frédéric [UCL] et al.[show all]

During liver development, hepatocytes and biliary cells differentiate from common progenitors called hepatoblasts. The factors that control hepatoblast fate decision are unknown. Here we report that a gradient of activin/TGFbeta signaling controls hepatoblast differentiation. High activin/TGFbeta signaling is required near the portal vein for differentiation of biliary cells. The Onecut transcription factors HNF-6 and OC-2 inhibit activin/TGFbeta signaling in the parenchyma, and this allows normal hepatocyte differentiation. In the absence of Onecut factors, the shape of the activin/TGFbeta gradient is perturbed and the hepatoblasts differentiate into hybrid cells that display characteristics of both hepatocytes and biliary cells. Thus, a gradient of activin/TGFbeta signaling modulated by Onecut factors is required to segregate the hepatocytic and the biliary lineages.