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

Research output: Contribution to journalArticle

  • Lara Plana-Paz
  • Vanessa Orsini
  • 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. Nicholson
  • Raffaella Zamponi
  • Paola Capodieci
  • Reginald Valdez
  • Daniel Rivera
  • Andreas Loew
  • Chinweike Ukomadu
  • Luigi M. Terracciano
  • Tewis Bouwmeester
  • Feng Cong
  • Markus H. Heim
  • Heinz Ruffner
  • Jan S. Tchorz

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


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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