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Cited by 202Liver physiology and pathologyWnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene Regulation

β-Catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development

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Tan, Xinping, Yuan, Youzhong, Zeng, Gang, Apte, Udayan, Thompson, Michael D., Cieply, Benjamin, Stolz, Donna B., Michalopoulos, George K. +2 more·2008·Hepatology
DOI 10.1002/hep.22225PMC PMC4449338
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Abstract

β-Catenin, the central component of the canonical Wnt pathway, plays important roles in the processes of liver regeneration, growth, and cancer. Previously, we identified temporal expression of β-catenin during liver development. Here, we characterize the hepatic phenotype, resulting from the successful deletion of β-catenin in the developing hepatoblasts utilizing Foxa3-cyclization recombination and floxed -β-catenin (exons 2 through 6) transgenic mice. β-Catenin loss in developing livers resulted in significantly underdeveloped livers after embryonic day 12 (E12) with lethality occurring at around E17 stages. Histology revealed an overall deficient hepatocyte compartment due to (1) increased cell death due to oxidative stress and apoptosis, and (2) diminished expansion secondary to decreased cyclin-D1 and impaired proliferation. Also, the remnant hepatocytes demonstrated an immature phenotype as indicated by high nuclear to cytoplasmic ratio, poor cell polarity, absent glycogen, and decreased expression of key liver-enriched transcription factors: CCAAT-enhancer binding protein-α and hepatocyte nuclear factor-4α. A paucity of primitive bile ducts was also observed. While the stem cell assays demonstrated no intrinsic defect in hematopoiesis, distorted hepatic architecture and deficient hepatocyte compartments resulted in defective endothelial cell organization leading to overall fetal pallor. Conclusion: β-Catenin regulates multiple, critical events during the process of hepatic morphogenesis, including hepatoblast maturation, expansion, and survival, making it indispensable to survival.

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  • GSTMs are glutathione S-transferase family members within the mu subfamily that are activated upon WNT and NRF2 signaling.

    “GSTMs are glutathione S-transferase family members within the mu subfamily that are activated upon WNT and NRF2 signaling (40–43).”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [42]

    The Results report that GST-mu1 expression decreased in β-catenin-deficient fetal mouse livers, supporting an association with Wnt/β-catenin signaling in that setting. The paper does not establish that Wnt directly activates GSTMs, and the passages found do not address NRF2 signaling. (LLM, conf=0.87)

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Cited by

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Authors
Tan, X., Yuan, Y., Zeng, G., Apte, U., Thompson, M. D., Cieply, B., Stolz, D. B., Michalopoulos, G. K., Kaestner, K. H., & Monga, S. P. S.
Affiliations
University of Pennsylvania (US)
Corresponding author
Monga, Satdarshan P.S.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2008-05
Volume
47
Issue
5
Pages
1667-1679
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.22225
PMC
PMC4449338
OpenAlex
W2055373965
Cited by
202
References
1
Citations by year
2026: 4 · 2025: 4 · 2024: 10 · 2023: 4 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 8 · 2018: 7 · 2017: 13 · 2016: 16 · 2015: 18 · 2014: 5 · 2013: 13 · 2012: 16
FWCI
14.43
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 2679 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (NIH) (1R01DK62277, R01CA124414)
  • Rango's Fund for Enhancement of Pathology Research; and the Cleveland Foundation
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
β-catenin, hepatoblasts, liver development, Wnt/β-catenin signaling, hepatocyte maturation, hepatocyte proliferation, apoptosis, oxidative stress, cyclin D1, C/EBPα, HNF4α, bile ducts, embryonic lethality
MeSH terms
alpha-Fetoproteins, Animals, Liver, Morphogenesis, RNA, Serum Albumin, Gene Deletion, Mice, Knockout, Gene Expression Regulation, Developmental, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, beta Catenin, Mice

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