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R-spondin controls liver zonation and size via Lgr4 and Lgr5 receptors

Planas Paz, Lara and Orsini, Vanessa and Calabrese, Diego and Boulter, Luke and Nigsch, Florian and Roma, Guglielmo and Bergling, Sebastian and Donovan, Adriana and Pikiolek, Monika and Marti, Patricia and Beckmann, Nicolau and Dill, Michael and Carbone, Walter and Isken, Andrea and Mueller, Matthias and Kinzel, Bernd and Yang, Yi and Capodieci, Paola and Valdez, Reginald and Rivera, Daniel and Loew, Andreas and Ukomadu, Chinweike and Xie, Yang and Zamponi, Raffaella and Terracciano, Luigi and Mao, Xiaohong and Nicholson, Thomas and Bouwmeester, Antonius and Cong, Feng and Heim, Markus and Forbes, Stuart and Ruffner, Heinz and Tchorz, Jan (0015) R-spondin controls liver zonation and size via Lgr4 and Lgr5 receptors. R-spondin controls liver zonation and size via Lgr4 and Lgr5 receptors .

Abstract

Lgr4/5 receptors and their RSPO ligands potentiate Wnt/β-Catenin signaling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-Catenin activity gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified a novel role for the RSPO-Lgr4/5-Znrf3/Rnf43 complex in establishing the hepatic Wnt/β-Catenin activity gradient and metabolic liver zonation. Liver-specific Lgr4/5 loss of function (LOF) or RSPO blockade disrupted the hepatic Wnt/β-Catenin activity and zonation. Conversely, pathway activation in Znrf3/Rnf43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt gradient in a reversible and Lgr4/5-dependent manner. Furthermore, we show that Znrf3/Rnf43 are gatekeepers for hepatic proliferation. Likewise, recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas Lgr4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Together, the RSPO-Lgr4/5-Znrf3/Rnf43 complex controls metabolic liver zonation and acts as a hepatic size rheostat during development and regeneration.

Item Type: Article
Date Deposited: 28 Apr 2016 23:45
Last Modified: 28 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27439

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