Control of liver cell fate decision by a gradient of TGF beta 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/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.
Clotman
Frédéric
F
Hormone and Metabolic Research Unit, Cell Biology Unit, Institute of Cellular Pathology and Université catholique de Louvain, Brussels, Belgium.
Jacquemin
Patrick
P
Plumb-Rudewiez
Nicolas
N
Pierreux
Christophe E
CE
Van der Smissen
Patrick
P
Dietz
Harry C
HC
Courtoy
Pierre J
PJ
Rousseau
Guy G
GG
Lemaigre
Frédéric P
FP
D028341:Activins / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005333:Fetus; D051559:Hepatocyte Nuclear Factor 6; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
D051559:Hepatocyte Nuclear Factor 6; D018398:Homeodomain Proteins; C487964:ONECUT2 protein, mouse; C496606:Onecut1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D028341:Activins