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Cited by 361Liver physiology and pathologyWnt/β-catenin signaling in development and cancerOrgan Transplantation Techniques and Outcomes

Conditional Deletion of β-Catenin Reveals Its Role in Liver Growth and Regeneration

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Tan, Xinping, Behari, Jaideep, Cieply, Benjamin, Michalopoulos, George K., Monga, Satdarshan P.S.·2006·Gastroenterology
DOI 10.1053/j.gastro.2006.08.042
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Abstract

Background & aims The Wnt/beta-catenin pathway plays a role in liver growth and development. To address this conclusively, we used a conditional knockout approach to delete beta-catenin in the liver. Methods Floxed beta-catenin (exons 2-6) mice were intercrossed with Albumin-Cre recombinase transgenic mice; considerable beta-catenin deletion was evident 15 days after birth by Western blot and immunohistochemistry analyses. Results Although these mice were viable, there was a significant decrease in their liver weight/body weight ratio by 14% at 1 month and 28%-35% by 2-6 months of age, which was sustained throughout their normal life span. There was an accompanying decrease in basal hepatocyte proliferation showed by Ki-67 staining. Additional analysis revealed several known and novel genes to be down-regulated in these mice that play a role in normal liver homeostasis. When subjected to two-thirds partial hepatectomy, the Ctnnb1(loxp/loxp); Alb-Cre(+/-) mice were sick and lethargic, especially during the first 2-3 days only. These mice display a 2-fold decrease in the number of Ki-67- or PCNA-positive cells at the time of peak hepatocyte proliferation at 40 hours, which coincided with decreased cyclin A, D, and E expression. However, a rebound increase in hepatocyte proliferation was evident in the knockout mice at 3 days. Also, increased apoptosis was observed in the knockout livers during regeneration at all stages. Conclusions Thus, beta-catenin is essential for normal liver growth and development. Also, although regeneration is delayed in the absence of beta-catenin, it does occur suboptimally, showing its redundancy in the liver.

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  • Mice with hepatocyte-specific deletion of Lgr4 alone, Lgr4 plus Lgr5 or β-catenin displayed alterations in liver size, zonation and regeneration, including hyperproliferation at late timepoints, similar to HSC-depleted mice.

    “Notably, mice with hepatocyte-specific deletion of the RSPO3 receptors Lgr4 alone, Lgr4 plus Lgr5 or their downstream target β-catenin displayed alterations in liver size, zonation and regeneration, including hyperproliferation at late timepoints, similar to HSC-depleted mice24,25.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [25]

    For the β-catenin deletion portion of the jointly cited sentence, the paper reports a lower liver-weight/body-weight ratio (Figure 2 caption), altered regeneration, and more Ki-67-positive hepatocytes than controls at 14 days after hepatectomy (Figure 7 caption; page unavailable). It reports reduced glutamine synthetase and other gene-expression changes, but the passages do not establish altered spatial liver zonation. The late proliferation finding is also limited: the Results say that only a few knockout hepatocytes remained Ki-67-positive. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • HSC-derived RSPO3 critically impacts liver size, zonation, metabolism, regeneration and injury.

    “The critical impact of HSC-derived RSPO3 on liver size, zonation, metabolism, regeneration and injury matches findings in mice with hepatocyte-specific deletion of β-catenin or LGR4/524,25,34–39, rendering RSPO3–LGR4-mediated HSC–hepatocyte communication a gatekeeper of liver function in health and disease.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [25]

    The paper reports that hepatocyte-specific β-catenin deletion reduces liver size, alters expression of metabolic enzymes, increases apoptosis, and delays regeneration after partial hepatectomy (Discussion; Differential Expression of Cytochrome P450 Enzymes; Conditional Null Mice After Two-Thirds Hepatectomy; page numbers unavailable). These findings support part of the cited comparison, but our copy does not establish effects on liver zonation or injury more broadly. It does not study HSC-derived RSPO3 or LGR4; the citing sentence does not attribute those experiments to this paper. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • RSPO3-LGR4-mediated HSC-hepatocyte communication is a gatekeeper of liver function in health and disease.

    “The critical impact of HSC-derived RSPO3 on liver size, zonation, metabolism, regeneration and injury matches findings in mice with hepatocyte-specific deletion of β-catenin or LGR4/524,25,34–39, rendering RSPO3–LGR4-mediated HSC–hepatocyte communication a gatekeeper of liver function in health and disease.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [25]

    The paper’s Discussion reports smaller livers and delayed, suboptimal regeneration after hepatocyte β-catenin deletion; its gene-array findings also show changes in metabolic genes. These support much of the cited comparison, but the copy does not establish altered liver zonation or a general response to injury beyond partial hepatectomy. The concluding RSPO3–LGR4 gatekeeper interpretation is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Hepatocytes in the postnatal liver expand rapidly in a Wnt/β-catenin signaling-dependent way.

    “Hepatocytes in the postnatal liver expand rapidly in a Wnt/β-catenin signaling-dependent way (12–16).”

    From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [13]

  • HSC-depleted livers exhibited compensatory hyperproliferation at later stages while HSC depletion persisted.

    “Like other mice with impaired liver regeneration24,25, HSC-depleted livers exhibited compensatory hyperproliferation at later stages, while HSC depletion persisted (Extended Data Fig. 1f).”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [25]

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Cited by

Sorted by citations

Authors
Tan, X., Behari, J., Cieply, B., Michalopoulos, G. K., & Monga, S. P. S.
Affiliations
University of Pittsburgh (US)
Corresponding author
Monga, Satdarshan P.S.
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2006-11
Volume
131
Issue
5
Pages
1561-1572
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2006.08.042
OpenAlex
W2048711000
Cited by
361
References
1
Citations by year
2026: 8 · 2025: 13 · 2024: 20 · 2023: 13 · 2022: 18 · 2021: 17 · 2020: 19 · 2019: 11 · 2018: 19 · 2017: 21 · 2016: 14 · 2015: 15 · 2014: 19 · 2013: 23 · 2012: 18
FWCI
15.42
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1RO1DK62277)
  • National Institute of Diabetes and Digestive and Kidney Diseases (1 R01 DK62277, R01DK062277)
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
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
β-catenin, Wnt/β-catenin signaling, liver growth, liver regeneration, conditional knockout, hepatocyte proliferation, partial hepatectomy, apoptosis, cyclins, liver development, liver homeostasis
MeSH terms
Animals, Cytochrome P-450 Enzyme System, Hepatectomy, Liver, Liver Regeneration, Male, Phenotype, Cadherins, Apoptosis, Mice, Knockout, Proliferating Cell Nuclear Antigen, Cell Proliferation, Wnt Proteins, beta Catenin, Mice

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