title: The Angiocrine Factor Rspondin3 Is a Key Determinant of Liver Zonation.
abstract: Liver zonation, the spatial separation of different metabolic pathways along the liver sinusoids, is fundamental for proper functioning of this organ, and its disruption can lead to the development of metabolic disorders such as hyperammonemia. Metabolic zonation involves the induction of β-catenin signaling around the central veins, but how this patterned activity is established and maintained is unclear. Here, we show that the signaling molecule Rspondin3 is specifically expressed within the endothelial compartment of the central vein. Conditional deletion of Rspo3 in mice disrupts activation of central fate, demonstrating its crucial role in determining and maintaining β-catenin-dependent zonation. Moreover, ectopic expression of Rspo1, a close family member of Rspo3, induces the expression of pericentral markers, demonstrating Rspondins to be sufficient to imprint a more central fate. Thus, Rspo3 is a key angiocrine factor that controls metabolic zonation of liver hepatocytes.
authors.affiliation: Institute of Biology Valrose, Université de Nice-Sophia, 06108 Nice, France; Inserm, UMR1091, 06108 Nice, France; CNRS, UMR7277, 06108 Nice, France. Electronic address: rocha@unice.fr.
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Rocha
authors.affiliation: Institute of Biology Valrose, Université de Nice-Sophia, 06108 Nice, France; Inserm, UMR1091, 06108 Nice, France; CNRS, UMR7277, 06108 Nice, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Vidal
authors.affiliation: Institute of Biology Valrose, Université de Nice-Sophia, 06108 Nice, France; Inserm, UMR1091, 06108 Nice, France; Plateforme PRISM, Institute of Biology Valrose, Université de Nice-Sophia, 06108 Nice, France.
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Mertz
authors.affiliation: MRC Human Genetics Unit, Western General Hospital Campus, Edinburgh, EH4 2XU Scotland, UK.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kendall
authors.affiliation: Institute of Biology Valrose, Université de Nice-Sophia, 06108 Nice, France; Inserm, UMR1091, 06108 Nice, France; CNRS, UMR7277, 06108 Nice, France.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Charlet
authors.affiliation: RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Institute of Biology Valrose, Université de Nice-Sophia, 06108 Nice, France; Inserm, UMR1091, 06108 Nice, France; CNRS, UMR7277, 06108 Nice, France. Electronic address: andreas.schedl@unice.fr.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schedl
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051154:Wnt2 Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D060466:Axin Protein; C111729:Axin2 protein, mouse; C493597:Lgr5 protein, mouse; C517523:R-spondin3 protein, mouse; D043562:Receptors, G-Protein-Coupled; D019699:Thrombospondins; D051153:Wnt Proteins; D051154:Wnt2 Protein; C515303:Wnt9b protein, mouse; D051176:beta Catenin; D013629:Tamoxifen