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

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/ TGF beta signaling controls hepatoblast differentiation. High activin/TGF beta signaling is required near the portal vein for differentiation of biliary cells. The Onecut transcription factors HNF-6 and OC-2 inhibit activin/TGF beta signaling in the parenchyma, and this allows normal hepatocyte differentiation. In the absence of Onecut factors, the shape of the activin/TGF beta gradient is perturbed and the hepatoblasts differentiate into hybrid cells that display characteristics of both hepatocytes and biliary cells. Thus, a gradient of activin/TGF beta signaling modulated by Onecut factors is required to segregate the hepatocytic and the biliary lineages.