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

Wnt/β-Catenin signaling regulates liver zonation and hepatocyte proliferation during development and regeneration. However, the instructive mechanisms controlling spatiotemporal regulation of Wnt signaling during these processes remain elusive. We now show that Lgr4 and Lgr5 receptors are co-expressed in pericentral hepatocytes with high Wnt activity. Liver-specific Lgr4 knockout (Lgr4LKO) or Lgr4/5 double KO (Lgr4/5dLKO) mice show loss of liver zonation as evidenced by loss of pericentral Glutamine synthetase (GS) expression and downregulation of gene sets for Wnt signaling and liver metabolism. Transgenic expression of the extracellular domain of ZNRF3, blocking endogenous Roof Plate-Specific Spondin (RSPO)-mediated Wnt pathway activation via Lgr4/5 receptors, phenocopies Lgr4/5 deletion. RSPO1 protein was expressed around the central but not portal veins. Intravenous RSPO1 protein injection extends the Wnt gradient via Lgr4/5 receptors. This suggests that pericentral Lgr4/5 receptors and a centro-portal RSPO1 gradient are responsible for liver zonation. Lgr4/5dLKO mice further show impaired liver size control during development and regeneration following partial hepatectomy (PH) as evidenced by impaired hepatocyte proliferation and downregulation of gene sets for Wnt signaling and mitosis. Loss of hepatocyte numbers is compensated by an increase in hepatocyte size. Regeneration zonation, characterized by differential hepatocyte proliferation in different hepatic zones, is lost in Lgr4/5dLKO mice. RSPO1 injection increases liver size and regeneration following PH by controlling hepatocyte proliferation. Together, our data establish that RSPO1 controls liver zonation via Lgr4/5 receptors 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/25133