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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.

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


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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