The Angiocrine Factor Rspondin3 Is a Key Determinant of Liver Zonation

Cell Rep. 2015 Dec 1;13(9):1757-64. doi: 10.1016/j.celrep.2015.10.049. Epub 2015 Nov 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axin Protein / genetics
  • Axin Protein / metabolism
  • Cell Line
  • Down-Regulation / drug effects
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Female
  • In Situ Hybridization, Fluorescence
  • Mice
  • Mice, Knockout
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Tamoxifen / pharmacology
  • Thrombospondins / genetics
  • Thrombospondins / metabolism*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / drug effects
  • Wnt2 Protein / genetics
  • Wnt2 Protein / metabolism
  • beta Catenin / metabolism


  • Axin Protein
  • Axin2 protein, mouse
  • Lgr5 protein, mouse
  • R-spondin3 protein, mouse
  • Receptors, G-Protein-Coupled
  • Thrombospondins
  • Wnt Proteins
  • Wnt2 Protein
  • Wnt9b protein, mouse
  • beta Catenin
  • Tamoxifen