Abstract
Background and AimsMorphological 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.MethodsGene 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.ResultsDynamic 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.ConclusionsMorphological 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.
Highlights
Morphological changes in developing human organs require coordinated activation of gene transcription and signaling pathways [1]
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
Summary
Morphological changes in developing human organs require coordinated activation of gene transcription and signaling pathways [1]. The epithelial cells lining the human esophagus transform from simple columnar into ciliated epithelium at an early phase. Studies using mouse genetic models provided initial insights into the roles of transcription factors and signaling pathways for the morphogenesis of the esophagus [4,5]. From postnatal day 7 (P7) onwards, the top layer of the stratified squamous epithelium starts the enucleating process and forms a keratin layer which is not present in the human esophagus [5,7,8,9]. Morphological changes during human and mouse esophageal development have been well characterized. This study aims to globally profile critical genes and signaling pathways during the development of mouse esophagus. By using microarray analysis this study aims to determine how the Nrf2/Keap pathway regulates the morphogenesis of the esophageal epithelium
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