The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size
Open accessAbstract
LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/β-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4(+) hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO-LGR4/5-ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration.
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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 [24]
The sections on liver zonation and regeneration (page unavailable) report reduced liver weight and altered zonation after liver-specific Lgr4 or Lgr4/5 deletion, and impaired early regeneration in both genotypes. They report increased proliferation at days 4 and 7 after partial hepatectomy for the Lgr4/5 double knockout, and describe a similar delayed onset in β-catenin knockout mice, but do not establish late hyperproliferation for Lgr4 deletion alone. The comparison with HSC-depleted mice is the citing authors’ framing, not a finding attributed to this source. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRSPO3 receptors Lgr4 and Lgr5 were enriched in hepatocytes.
“Conversely, RSPO3 receptors Lgr4 and Lgr5 were enriched in hepatocytes (Extended Data Fig. 6d), as described previously24.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [24]
The main text (Figure 1f–g) reports Lgr4 expression in virtually all hepatocytes and Lgr5 expression mainly in pericentral hepatocytes. This supports their expression in hepatocytes, but the cited passages do not establish enrichment relative to other liver cell types; Lgr5 is also not broadly expressed across hepatocytes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredHSC-derived RSPO3, hepatocyte-expressed LGR4 and its downstream target β-catenin are central mediators of the HSC-hepatocyte cross-talk that controls liver size, zonation and function.
“Thus, Rspo3ΔHSC mice reproduced key aspects of HSC-depleted, Lgr4/Lgr5ΔHep and Ctnnb1ΔHep mice24,25,34–39, suggesting HSC-derived RSPO3, hepatocyte-expressed LGR4 and its downstream target β-catenin as central mediators of the HSC–hepatocyte cross-talk that controls liver size, zonation and function.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [24]
The Discussion (page unavailable) supports a central role for LGR4/5-dependent Wnt/β-catenin signalling in liver zonation and size control. But it says the source and distribution of hepatic RSPO proteins remained to be identified; it does not establish HSC-derived RSPO3 or HSC–hepatocyte cross-talk. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLiver zonation and functions are regulated by a 'ménage à trois' of WNT-secreting ECs, RSPO3-secreting HSCs and hepatocytes expressing the R-spondin receptors LGR4 and LGR5.
“Our data amend the purely angiocrine model of liver zonation29,41,56,57 and suggest that liver zonation and functions are regulated by a ‘ménage à trois’ of WNT-secreting ECs, RSPO3-secreting HSCs and hepatocytes expressing the R-spondin receptors LGR4 and LGR524.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [24]
The sections on RSPO control of liver zonation and the Discussion support a role for hepatocyte LGR4/5 receptors and RSPO signalling in metabolic liver zonation. But the Discussion says the source and distribution of RSPO proteins remained unidentified; this paper therefore does not establish the claimed RSPO3-secreting HSCs or the full three-cell model. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHSC-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 [24]
The liver-specific Lgr4/5 knockout results and the Discussion show effects on liver size, metabolic zonation, and regeneration, supporting the cited comparison with LGR4/5 deletion. The paper studies LGR4/5 signaling and recombinant RSPO1, not HSC-derived RSPO3, and the cited passages do not establish an effect of HSC-derived RSPO3 on liver injury. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Previous studies using global knockout or overexpression found that RSPO3 is an important regulator of liver zonation and hepatocyte proliferation, but did not dissect its cell-specific functions and its key role in HSC-hepatocyte cross-talk.
“Previous studies, using global knockout or overexpression, have found that RSPO3 is an important regulator of liver zonation and hepatocyte proliferation, but did not dissect its cell-specific functions and its key role in the HSC–hepatocyte cross-talk24,41,55.”
From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [24]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredActivation 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 [44]
The results section (page unavailable) reports that RSPO1 expanded WNT/β-catenin signalling into periportal hepatocytes and increased the pericentral markers GS and CYP2E1, but does not establish that those cells were fully reprogrammed. Another results passage reports increased periportal metabolic genes after β-catenin knockout or DKK1 overexpression, but says they were not increased after LGR4/5 deletion. Thus the effect of pathway blockage depends on how it was blocked, and the copy does not establish widespread periportal enzyme expression for blockage generally. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDue to high levels of WNT/β-catenin signalling, pericentral hepatocytes express the β-catenin target gene Lgr5, which confers tissue stem cell identity in the gut, but not in the liver.
“Due to high levels of WNT/β-catenin signalling, pericentral hepatocytes express the β-catenin target gene Lgr5, which confers tissue stem cell identity in the gut, but not in the liver.44,50”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [44]
The main text (page unavailable) identifies LGR5 as a Wnt target gene expressed in pericentral hepatocytes with high Wnt activity. The Discussion (page unavailable) reports that these cells did not show the proliferation or outward lineage expansion seen in other LGR5-positive tissue stem-cell compartments. It does not establish that LGR5 itself confers stem-cell identity in the gut; it describes LGR5 as expressed in those stem cells. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTreatment with RSPO ligands or tetravalent FZD-LRP antibodies enhanced WNT/β-catenin signalling, accelerated liver regeneration and increased metabolic function in diverse injury models.
“Treatment with RSPO ligands44,158 or tetravalent FZD-LRP antibodies25 enhanced WNT/β-catenin signalling, accelerated liver regeneration and increased metabolic function in diverse injury models.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [44]
The RSPO1-treatment passages report increased hepatic WNT/β-catenin signalling and faster liver regrowth after partial hepatectomy. They also report changes in metabolic-zonation markers, but not improved metabolic function; the treatment experiment uses one regeneration model, not diverse injury models. The tetravalent-antibody claim is attached to a different citation in the citing sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHepatocytes 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 [15]
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 [24]
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 [24]
Alternative zone 3 labelling with other gene promoters also did not show that zone 3 hepatocytes give rise to hepatocytes in other zones during homeostasis.
“Alternative zone 3 labelling with other gene promoters also did not show that zone 3 hepatocytes give rise to hepatocytes in other zones during homeostasis.44,50,86”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [44]
RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.
“RSPO injections reversibly increased liver size by inducing hepatocyte proliferation, whereas WNT/β-catenin signalling blockade resulted in smaller livers.44,90,91”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [44]
The RSPO-LGR4/5-ZNRF3/RNF43 module controlling WNT/β-catenin signalling is a growth and size rheostat in the liver.
“The RSPO-LGR4/5-ZNRF3/RNF43 module controlling WNT/β-catenin signalling is a growth and size rheostat in the liver.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [44]
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Liver macrophages: development, dynamics, and functions
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Tissue-targeted R-spondin mimetics for liver regeneration
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- Authors
- Planas-Paz, L., Orsini, V., Boulter, L., Calabrese, D., Pikiolek, M., Nigsch, F., Xie, Y., Roma, G., Donovan, A., Marti, P., Beckmann, N., Dill, M. T., Carbone, W., Bergling, S., Isken, A., Mueller, M., Kinzel, B., Yang, Y., Mao, X., Nicholson, T. B., Zamponi, R., Capodieci, P., Valdez, R., Rivera, D., Loew, A., Ukomadu, C., Terracciano, L. M., Bouwmeester, T., Cong, F., Heim, M. H., Forbes, S. J., Ruffner, H., & Tchorz, J. S.
- Affiliations
- Novartis (Switzerland) (CH)
- Institute of Genetics and Cancer (GB)
- University Hospital of Basel (CH)
- MRC Centre for Regenerative Medicine (GB)
- Corresponding author
- Tchorz, Jan S.
- ORCID
- Boulter, Luke
- Calabrese, Diego
- Nigsch, Florian
- Xie, Yang
- Roma, Guglielmo
- Beckmann, Nicolau
- Dill, Michael T.
- Carbone, Walter
- Bergling, Sebastian
- Mueller, Matthias
- Yang, Yi
- Nicholson, Thomas B.
- Zamponi, Raffaella
- Capodieci, Paola
- Valdez, Reginald
- Rivera, Daniel
- Loew, Andreas
- Ukomadu, Chinweike
- Terracciano, Luigi M.
- Bouwmeester, Tewis
- Cong, Feng
- Heim, Markus H.
- Forbes, Stuart J.
- Ruffner, Heinz
- Tchorz, Jan S.
- Venue
- Nature Cell Biology
- Published
- 2016-04-18
- Volume
- 18
- Issue
- 5
- Pages
- 467-479
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2339774221
- Cited by
- 359
- References
- 58
- Citations by year
- 2026: 29 · 2025: 35 · 2024: 35 · 2023: 27 · 2022: 45 · 2021: 36 · 2020: 44 · 2019: 30 · 2018: 36 · 2017: 29 · 2016: 13
- FWCI
- 18.72
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-10-27)
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- edoc (University of Basel) (submittedVersion)
- Funders
- Leverhulme Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (147089)
- Novartis Institutes for BioMedical Research
- Medical Research Council (MR/K026666, MR/K026666/1)
- 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 › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- RSPO1, Wnt/β-catenin signaling, liver zonation, liver regeneration, hepatocyte proliferation, liver homeostasis
- MeSH terms
- Animals, Animals, Newborn, beta-Galactosidase, Homeostasis, Liver, Liver Regeneration, Organ Size, Signal Transduction, Gene Deletion, Cell Lineage, Cytochrome P-450 CYP2E1, Ki-67 Antigen, Thrombospondins, Hepatocytes, Receptors, G-Protein-Coupled, Ubiquitin-Protein Ligases, Cell Proliferation
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