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

Lara Plana-Paz, Vanessa Orsini, Luke Boulter, Diego Calabrese, Monika Pikiolek, Florian Nigsch, Yang Xie, Guglielmo Roma, Adriana Donovan, Patricia Marti, Nicolau Beckmann, Michael T. Dill, Walter Carbone, Sebastian Bergling, Andrea Isken, Matthias Mueller, Bernd Kinzel, Yi Yang, Xiaohong Mao, Thomas B. NicholsonRaffaella Zamponi, Paola Capodieci, Reginald Valdez, Daniel Rivera, Andreas Loew, Chinweike Ukomadu, Luigi M. Terracciano, Tewis Bouwmeester, Feng Cong, Markus H. Heim, Stuart J. Forbes, Heinz Ruffner, Jan S. Tchorz

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)467–479
Number of pages13
JournalNature Cell Biology
Issue number5
Early online date18 Apr 2016
Publication statusPublished - May 2016


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