Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration.

Academic Article


  • Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced β-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and β-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway.
  • Authors

  • Nakamura, Ikuo
  • Fernandez-Barrena, Maite G
  • Ortiz-Ruiz, Maria C
  • Almada, Luciana L
  • Hu, Chunling
  • Elsawa, Sherine
  • Mills, Lisa D
  • Romecin, Paola A
  • Gulaid, Kadra H
  • Moser, Catherine D
  • Han, Jing-Jing
  • Vrabel, Anne
  • Hanse, Eric A
  • Akogyeram, Nicholas A
  • Albrecht, Jeffrey H
  • Monga, Satdarshan PS
  • Sanderson, Schuyler O
  • Prieto, Jesus
  • Roberts, Lewis R
  • Fernandez-Zapico, Martin E
  • Status

    Publication Date

  • July 19, 2013
  • Published In


  • Animals
  • Cell Proliferation
  • Down-Regulation
  • Gene Knockout
  • Hedgehog Proteins
  • Hepatectomy
  • Hepatocytes
  • Kruppel-Like Transcription Factors
  • Liver
  • Liver Regeneration
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Regeneration
  • Sulfatases
  • Transcription Factors
  • Wnt Signaling
  • Wnt Signaling Pathway
  • Wnt3A Protein
  • Zinc Finger Protein GLI1
  • beta Catenin
  • Digital Object Identifier (doi)

    Start Page

  • 21389
  • End Page

  • 21398
  • Volume

  • 288
  • Issue

  • 29