Apc Tumor Suppressor Gene Is the “Zonation-Keeper” of Mouse Liver
Open accessAbstract
The molecular mechanisms by which liver genes are differentially expressed along a portocentral axis, allowing for metabolic zonation, are poorly understood. We provide here compelling evidence that the Wnt/beta-catenin pathway plays a key role in liver zonation. First, we show the complementary localization of activated beta-catenin in the perivenous area and the negative regulator Apc in periportal hepatocytes. We then analyzed the immediate consequences of either a liver-inducible Apc disruption or a blockade of Wnt signaling after infection with an adenovirus encoding Dkk1, and we show that Wnt/beta-catenin signaling inversely controls the perivenous and periportal genetic programs. Finally, we show that genes involved in the periportal urea cycle and the perivenous glutamine synthesis systems are critical targets of beta-catenin signaling, and that perturbations to ammonia metabolism are likely responsible for the death of mice with liver-targeted Apc loss. From our results, we propose that Apc is the liver "zonation-keeper" gene.
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Wnt target genes and key metabolic enzymes have a zonated expression pattern in pericentral hepatocytes.
“creating a zonated expression pattern of Wnt target genes and key metabolic enzymes in pericentral hepatocytes (20–22).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [20]
Activation of WNT/β-catenin signalling reprogrammed periportal into pericentral hepatocytes, while pathway blockage induced widespread periportal metabolic enzyme expression.
“While activation of WNT/β-catenin signalling reprogrammed periportal into pericentral hepatocytes, pathway blockage induced widespread periportal metabolic enzyme expression.22,42,44,45,51”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [42]
WNT/β-catenin signalling controlled by the RSPO-LGR4/5-ZNRF3/RNF43 module is a major determinant of hepatocyte identity and metabolic function in the liver.
“WNT/β-catenin signalling controlled by the RSPO-LGR4/5-ZNRF3/RNF43 module is a major determinant of hepatocyte identity and metabolic function in the liver.22,[42], [43], [44], [45], [46], [47], [48]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [42]
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- Authors
- Benhamouche, S., Decaens, T., Godard, C., Chambrey, R., Rickman, D. S., Moinard, C., Vasseur-Cognet, M., Kuo, C. J., Kahn, A., Perret, C., & Colnot, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- La Ligue Contre le Cancer (FR)
- Université Paris Cité (FR)
- Stanford Medicine (US)
- Corresponding author
- Perret, Christine
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2006-06
- Volume
- 10
- Issue
- 6
- Pages
- 759-770
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W1974549459
- Cited by
- 543
- References
- 0
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 31 · 2023: 28 · 2022: 35 · 2021: 25 · 2020: 37 · 2019: 36 · 2018: 32 · 2017: 30 · 2016: 26 · 2015: 22 · 2014: 27 · 2013: 27 · 2012: 24
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2603 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Association Nationale de la Recherche et de la Technologie
- Ligue Contre le Cancer
- Institut National de la Santé et de la Recherche Médicale
- Changshu Institute of Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- liver zonation, Wnt/β-catenin signaling, periportal hepatocytes, perivenous hepatocytes, DKK1, urea cycle, glutamine synthesis, ammonia metabolism, hepatic gene expression, hepatocyte differentiation
- MeSH terms
- Adenoviridae, Ammonia, Animals, Gene Expression Regulation, Genetic Vectors, Liver, Mice, Transgenic, Models, Biological, Nitrogen, Urea, Signal Transduction, Genes, Tumor Suppressor, Genes, APC, Mice, Knockout, Hepatocytes, Adenomatous Polyposis Coli Protein, Intercellular Signaling Peptides and Proteins, Wnt Proteins, beta Catenin, Mice
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