title: Nuclear Factor I-C acts as a regulator of hepatocyte proliferation at the onset of liver regeneration.
abstract: OBJECTIVE
  Knockout studies of the murine Nuclear Factor I-C (NFI-C) transcription factor revealed abnormal skin wound healing and growth of its appendages, suggesting a role in controlling cell proliferation in adult regenerative processes. Liver regeneration following partial hepatectomy (PH) is a well-established regenerative model whereby changes elicited in hepatocytes lead to their rapid and phased proliferation. Although NFI-C is highly expressed in the liver, no hepatic function was yet established for this transcription factor. This study aimed to determine whether NFI-C may play a role in hepatocyte proliferation and liver regeneration.
  
  
  METHODS
  Liver regeneration and cell proliferation pathways following two-thirds PH were investigated in NFI-C knockout (ko) and wild-type (wt) mice.
  
  
  RESULTS
  We show that the absence of NFI-C impaired hepatocyte proliferation because of plasminogen activator I (PAI-1) overexpression and the subsequent suppression of urokinase plasminogen activator (uPA) activity and hepatocyte growth factor (HGF) signalling, a potent hepatocyte mitogen. This indicated that NFI-C first acts to promote hepatocyte proliferation at the onset of liver regeneration in wt mice. The subsequent transient down regulation of NFI-C, as can be explained by a self-regulatory feedback loop with transforming growth factor beta 1 (TGF-ß1), may limit the number of hepatocytes entering the first wave of cell division and/or prevent late initiations of mitosis.
  
  
  CONCLUSIONS
  NFI-C acts as a regulator of the phased hepatocyte proliferation during liver regeneration.
authors.affiliation: Institute of Biotechnology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Edelmann
authors.forename: René
authors.initials: R
authors.lastname: Fahrner
authors.forename: Thomas
authors.initials: T
authors.lastname: Malinka
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Song
authors.forename: Deborah
authors.initials: D
authors.lastname: Stroka
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mermod
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D005838:Genotype; D006498:Hepatectomy / Q000379:methods; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: C553307:HGF protein, mouse; D051839:NFI Transcription Factors; C497648:Nfic protein, mouse; D017395:Plasminogen Activator Inhibitor 1; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D014568:Urokinase-Type Plasminogen Activator
keywords: NFI; PAI-1; TGF-ß1; partial hepatectomy; proliferation; tissue regeneration; urokinase