title: Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors.
abstract: 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.
authors.affiliation: Hormone and Metabolic Research Unit, Cell Biology Unit, Institute of Cellular Pathology and Université catholique de Louvain, Brussels, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Clotman
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Plumb-Rudewiez
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
authors.forename: Patrick
authors.initials: P
authors.lastname: Van der Smissen
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Courtoy
authors.forename: Guy G
authors.initials: GG
authors.lastname: Rousseau
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
mesh_terms: 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*
chemical_list: 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