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Nat Cell Biol. 2016 May;18(5):467-79. doi: 10.1038/ncb3337. Epub 2016 Apr 18.

The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size.

Author information

1
Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
2
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
3
Division of Gastroenterology and Hepatology, University Hospital Basel, 4031 Basel, Switzerland.
4
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
5
Institute for Pathology, University Hospital Basel, 4031 Basel, Switzerland.
6
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.

Abstract

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.

PMID:
27088858
DOI:
10.1038/ncb3337
[Indexed for MEDLINE]

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