title: The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Lara
authors.initials: L
authors.lastname: Planas-Paz
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Orsini
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, EH4 2XU Edinburgh, UK.
authors.forename: Luke
authors.identifier: 0000-0002-7954-6705
authors.initials: L
authors.lastname: Boulter
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Diego
authors.identifier: 0000-0002-0259-8611
authors.initials: D
authors.lastname: Calabrese
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Pikiolek
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Nigsch
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Roma
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Donovan
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: Marti
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Nicolau
authors.initials: N
authors.lastname: Beckmann
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Dill
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Walter
authors.initials: W
authors.lastname: Carbone
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bergling
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Isken
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Mao
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Nicholson
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Zamponi
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Capodieci
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Reginald
authors.initials: R
authors.lastname: Valdez
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rivera
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Loew
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Chinweike
authors.initials: C
authors.lastname: Ukomadu
authors.affiliation: Institute for Pathology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts 02139, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Markus H
authors.identifier: 0000-0002-7523-4894
authors.initials: MH
authors.lastname: Heim
authors.affiliation: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Heinz
authors.initials: H
authors.lastname: Ruffner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4056 Basel, Switzerland.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Tchorz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019070:Cell Lineage; D049109:Cell Proliferation; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D017353:Gene Deletion; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D008115:Liver Regeneration; D009929:Organ Size; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D019699:Thrombospondins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019394:Ki-67 Antigen; C496200:LGR4 protein, mouse; C493597:Lgr5 protein, mouse; C518903:RSPO1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins; D019392:Cytochrome P-450 CYP2E1; C575493:RNF43 protein, mouse; D044767:Ubiquitin-Protein Ligases; C572951:Znrf3 protein, mouse; D001616:beta-Galactosidase