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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Activins / antagonists & inhibitors
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Activins / physiology
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Animals
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Cell Differentiation / genetics
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Cell Differentiation / physiology
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Fetus
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Hepatocyte Nuclear Factor 6
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Hepatocytes / cytology
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Hepatocytes / physiology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Homeodomain Proteins / physiology*
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Mice
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Mice, Knockout
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Mice, Transgenic
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Trans-Activators / metabolism*
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / physiology*
Substances
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Hepatocyte Nuclear Factor 6
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Homeodomain Proteins
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ONECUT2 protein, mouse
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Onecut1 protein, mouse
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Activins