title: Hedgehog signalling stimulates precursor cell accumulation and impairs epithelial maturation in the murine oesophagus.
abstract: OBJECTIVE
  In the intestine Hedgehog (Hh) signalling is directed from epithelium to mesenchyme and negatively regulates epithelial precursor cell fate. The role of Hh signalling in the oesophagus has not been studied in vivo. Here the authors examined the role of Hh signalling in epithelial homeostasis of oesophagus.
  
  
  METHODS
  The authors used transgenic mice in which the Hh receptor Patched1 (Ptch1) could be conditionally inactivated in a body-wide manner and mice in which Gli1 could be induced specifically in the epithelium of the skin and oesophagus. Effects on epithelial homeostasis of the oesophagus were examined using immunohistochemistry, in situ hybridisation, transmission electron microscopy and real-time PCR. Hh signalling was examined in patients with oesophageal squamous cell carcinoma (SCC) by quantitative real-time PCR.
  
  
  RESULTS
  Sonic Hh is signalled in an autocrine manner in the basal layer of the oesophagus. Activation of Hh signalling resulted in an expansion of the epithelial precursor cell compartment and failure of epithelial maturation and migration. Levels of Hh targets GLI1, HHIP and PTCH1 were increased in SCC compared with normal tissue from the same patients.
  
  
  CONCLUSIONS
  Here the authors find that Hh signalling positively regulates the precursor cell compartment in the oesophageal epithelium in an autocrine manner. Since Hh signalling targets precursor cells in the oesophageal epithelium and signalling is increased in SCCs, Hh signalling may be involved in oesophageal SCC formation.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Willemijn A
authors.initials: WA
authors.lastname: van Dop
authors.forename: Sanne L
authors.initials: SL
authors.lastname: Rosekrans
authors.forename: Anja
authors.initials: A
authors.lastname: Uhmann
authors.forename: Viljar
authors.initials: V
authors.lastname: Jaks
authors.forename: G Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Marius A
authors.initials: MA
authors.lastname: van den Bergh Weerman
authors.forename: Maria
authors.initials: M
authors.lastname: Kasper
authors.forename: Jarom
authors.initials: J
authors.lastname: Heijmans
authors.forename: James C H
authors.initials: JC
authors.lastname: Hardwick
authors.forename: Hein W
authors.initials: HW
authors.lastname: Verspaget
authors.forename: Daan W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
authors.forename: Heidi
authors.initials: H
authors.lastname: Hahn
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism; D004947:Esophagus / Q000166:cytology*; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D053823:Hedgehog Proteins