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

Genes Dev. 2005 Aug 15;19(16):1849-54. doi: 10.1101/gad.340305.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activins / antagonists & inhibitors
  • Activins / physiology
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Fetus
  • Hepatocyte Nuclear Factor 6
  • Hepatocytes / cytology
  • Hepatocytes / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Homeodomain Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Trans-Activators / metabolism*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / physiology*


  • Hepatocyte Nuclear Factor 6
  • Homeodomain Proteins
  • ONECUT2 protein, mouse
  • Onecut1 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor beta
  • Activins