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Cited by 588Liver physiology and pathologyDevelopmental Biology and Gene RegulationHepatocellular Carcinoma Treatment and Prognosis

Hepatocyte nuclear factor 4α controls the development of a hepatic epithelium and liver morphogenesis

Parviz, Fereshteh, Matullo, Christine, Garrison, Wendy D, Savatski, Laura, Adamson, John W, Ning, Gang, Kaestner, Klaus H, Rossi, Jennifer M +2 more·2003·Nature Genetics
DOI 10.1038/ng1175
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Abstract

Although advances have been made in understanding cell differentiation, only rudimentary knowledge exists concerning how differentiated cells form tissues and organs. We studied liver organogenesis because the cell and tissue architecture of this organ is well defined. Approximately 60% of the adult liver consists of hepatocytes that are arranged as single-cell anastomosing plates extending from the portal region of the liver lobule toward the central vein. The basal surface of the hepatocytes is separated from adjacent sinusoidal endothelial cells by the space of Disse, where the exchange of substances between serum and hepatocytes takes place. The hepatocyte's apical surface forms bile canaliculi that transport bile to the hepatic ducts. Proper liver architecture is crucial for hepatic function and is commonly disrupted in disease states, including cirrhosis and hepatitis. Here we report that hepatocyte nuclear factor 4alpha (Hnf4alpha) is essential for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium. We show that Hnf4alpha is a dominant regulator of the epithelial phenotype because its ectopic expression in fibroblasts induces a mesenchymal-to-epithelial transition. Most importantly, the morphogenetic parameters controlled by Hnf4alpha in hepatocytes are essential for normal liver architecture, including the organization of the sinusoidal endothelium.

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  • HNF4A is necessary for hepatocyte differentiation; in Hnf4a null embryos rescued by tetraploid methodology, liver specification occurs but hepatocyte precursors fail to differentiate.

    “In this context, liver specification occurs in Hnf4a null embryos; however, hepatocyte precursors fail to differentiate (Parviz et al., 2003).”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Parviz et al., 2003

  • HNF4A has previously been implicated in regulating tissue remodeling, which is required for normal liver formation.

    “HNF4A has previously been implicated in regulating tissue remodeling, which is required for normal liver formation.”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Parviz et al., 2003

  • Ablation of HNF4A specifically in the embryonic liver causes loss of cohesive tissue architecture with disruption of cell-cell junction assembly.

    “Ablation of HNF4A specifically in the embryonic liver causes loss of cohesive tissue architecture with disruption of cell-cell junction assembly (Battle et al., 2006; Parviz et al., 2003).”

    From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Parviz et al., 2003

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Authors
Parviz, F., Matullo, C., Garrison, W. D., Savatski, L., Adamson, J. W., Ning, G., Kaestner, K. H., Rossi, J. M., Zaret, K. S., & Duncan, S. A.
Affiliations
  • Medical College of Wisconsin (US)
  • Fox Chase Cancer Center (US)
  • University of Pennsylvania (US)
Corresponding author
Duncan, Stephen A
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2003-06-15
Volume
34
Issue
3
Pages
292-296
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng1175
OpenAlex
W2038747312
Cited by
588
References
0
Citations by year
2026: 9 · 2025: 10 · 2024: 28 · 2023: 27 · 2022: 37 · 2021: 26 · 2020: 31 · 2019: 32 · 2018: 24 · 2017: 20 · 2016: 22 · 2015: 26 · 2014: 20 · 2013: 35 · 2012: 22
FWCI
14.77
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
HNF4α, liver organogenesis, liver morphogenesis, hepatocyte differentiation, mesenchymal-epithelial transition, hepatic glycogen storage, sinusoidal endothelium, space of Disse, bile canaliculi, liver architecture
MeSH terms
Animals, Cell Differentiation, Cell Division, Cells, Cultured, DNA-Binding Proteins, Epithelium, Female, Flow Cytometry, Immunoenzyme Techniques, Liver, Liver Glycogen, Male, Morphogenesis, Phosphoproteins, Pregnancy, Retroviridae, Transcription Factors, Transfection, Immunoblotting, Gene Expression, Apoptosis, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, Hepatocytes, Mice, Hepatocyte Nuclear Factor 4, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

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