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

Planas-Paz, Lara and Orsini, Vanessa and Boulter, Luke and Calabrese, Diego and Pikiolek, Monika and Nigsch, Florian and Xie, Yang and Roma, Guglielmo and Donovan, Adriana and Marti, Patricia and Beckmann, Nicolau and Dill, Michael T. and Carbone, Walter and Bergling, Sebastian and Isken, Andrea and Mueller, Matthias and Kinzel, Bernd and Yang, Yi and Mao, Xiaohong and Nicholson, Thomas B. and Zamponi, Raffaella and Capodieci, Paola and Valdez, Reginald and Rivera, Daniel and Loew, Andreas and Ukomadu, Chinweike and Terracciano, Luigi M. and Bouwmeester, Tewis and Cong, Feng and Heim, Markus H. and Forbes, Stuart J. and Ruffner, Heinz and Tchorz, Jan S.. (2016) The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature Cell Biology , 18 (5). pp. 467-479.

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Official URL: https://edoc.unibas.ch/61770/

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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.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Hepatology Laboratory (Heim)
UniBasel Contributors:Calabrese, Diego and Heim, Markus H.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Macmillan Publishers Limited
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:23 Jul 2020 12:05
Deposited On:23 Jul 2020 12:05

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