title: WNT5A inhibits hepatocyte proliferation and concludes β-catenin signaling in liver regeneration.
abstract: Activation of Wnt/β-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased β-catenin-T-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in β-catenin-T-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression. In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of β-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses β-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Ri.MED Foundation, Palermo, Italy; Institute of Biomedicine and Molecular Immunology Alberto Monroy, National Research Council, Palermo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cusimano
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jappmann K
authors.initials: JK
authors.lastname: Monga
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Morgan E
authors.initials: ME
authors.lastname: Preziosi
authors.affiliation: Ri.MED Foundation, Palermo, Italy; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pullara
authors.affiliation: Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Calero
authors.affiliation: Visual Systems Group, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Richard
authors.initials: R
authors.lastname: Lang
authors.affiliation: Cancer and Developmental Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, NIH, Frederick, Maryland.
authors.forename: Terry P
authors.initials: TP
authors.lastname: Yamaguchi
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Kari N
authors.initials: KN
authors.lastname: Nejak-Bowen
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Electronic address: smonga@pitt.edu.
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; C489743:Fzd2 protein, mouse; C545200:Gpr177 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin