title: Transcript profiling identifies dynamic gene expression patterns and an important role for Nrf2/Keap1 pathway in the developing mouse esophagus.
abstract: OBJECTIVE
  Morphological changes during human and mouse esophageal development have been well characterized. However, changes at the molecular level in the course of esophageal morphogenesis remain unclear. This study aims to globally profile critical genes and signaling pathways during the development of mouse esophagus. By using microarray analysis this study also aims to determine how the Nrf2/Keap1 pathway regulates the morphogenesis of the esophageal epithelium.
  
  
  METHODS
  Gene expression microarrays were used to survey gene expression in the esophagus at three critical phases: specification, metaplasia and maturation. The esophagi were isolated from wild-type, Nrf2(-/-), Keap1(-/-), or Nrf2(-/-)Keap1(-/-) embryos or young adult mice. Array data were statistically analyzed for differentially expressed genes and pathways. Histochemical and immunohistochemical staining were used to verify potential involvement of the Wnt pathway, Pparβ/δ and the PI3K/Akt pathway in the development of esophageal epithelium.
  
  
  RESULTS
  Dynamic gene expression patterns accompanied the morphological changes of the developing esophagus at critical phases. Particularly, the Nrf2/Keap1 pathway had a baseline activity in the metaplasia phase and was further activated in the maturation phase. The Wnt pathway was active early and became inactive later in the metaplasia phase. In addition, Keap1(-/-) mice showed increased expression of Nrf2 downstream targets and genes involved in keratinization. Microarray and immunostaining data also suggested that esophageal hyperkeratosis in the Keap1(-/-) mice was due to activation of Pparβ/δ and the PI3K/Akt pathway.
  
  
  CONCLUSIONS
  Morphological changes of the esophageal epithelium are associated with dynamic changes in gene expression. Nrf2/Keap1 pathway activity is required for maturation of mouse esophageal epithelium.
authors.affiliation: Cancer Research Program, JLC-BBRI, North Carolina Central University, Durham, North Carolina, United States of America.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Jianying
authors.initials: J
authors.lastname: Li
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Hu
authors.forename: Whitney
authors.initials: W
authors.lastname: Tevebaugh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Jianwen
authors.initials: J
authors.lastname: Que
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004947:Esophagus / Q000254:growth & development* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2