title: Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration.
abstract: 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.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nakamura
authors.affiliation: the Schulze Center for Novel Therapeutics and.
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.affiliation: the Departamento de Fisiología Facultad de Medicina Universidad de Murcia, 30100 Murcia, Spain.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Ortiz-Ruiz
authors.affiliation: the Schulze Center for Novel Therapeutics and.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905.
authors.forename: Chunling
authors.initials: C
authors.lastname: Hu
authors.affiliation: the Department of Biological Sciences, Northern Illinois University, Illinois 60115.
authors.forename: Sherine F
authors.initials: SF
authors.lastname: Elsawa
authors.affiliation: the Schulze Center for Novel Therapeutics and.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Mills
authors.affiliation: the Departamento de Fisiología Facultad de Medicina Universidad de Murcia, 30100 Murcia, Spain.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Romecin
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905.
authors.forename: Kadra H
authors.initials: KH
authors.lastname: Gulaid
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.affiliation: the Schulze Center for Novel Therapeutics and.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Han
authors.affiliation: the Schulze Center for Novel Therapeutics and.
authors.forename: Anne
authors.initials: A
authors.lastname: Vrabel
authors.affiliation: the Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55404.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hanse
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Akogyeram
authors.affiliation: the Division of Gastroenterology, Hennepin County Medical Center, Minneapolis, Minnesota 55404.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Albrecht
authors.affiliation: the Departments of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15216, and.
authors.forename: Satdarshan P S
authors.initials: SPS
authors.lastname: Monga
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Schuyler O
authors.initials: SO
authors.lastname: Sanderson
authors.affiliation: the Centro de Investigacion Medica Aplicada, 31008 Pamplona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905,. Electronic address: roberts.lewis@mayo.edu.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: From the Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, Minnesota 55905,; the Schulze Center for Novel Therapeutics and. Electronic address: fernandezzapico.martin@mayo.edu.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008115:Liver Regeneration / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D013429:Sulfatases / Q000172:deficiency / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D060509:Wnt3A Protein / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000378:metabolism
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D060509:Wnt3A Protein; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; C514911:Sulf2 protein, mouse; D013429:Sulfatases
keywords: Gene Knockout; Liver; Regeneration; Transcription Factors; Wnt Signaling