The dissertation was to understand cellular and molecular mechanisms underlying lung morphogenesis and repair. TAZ, a transcriptional co-activator, was co-expressed with TTF-1 and surfactant protein C (SP-C) in the respiratory epithelial cells during lung morphogenesis. TAZ enhanced the transcriptional activity of TTF-1 on the mouse SP-C promoter and interacted with NH2 –domain of TTF-1 that contains a TAZ binding motif. These findings support the concept that TAZ plays a role in regulating TTF-1-mediated expression of SP-C in the respiratory epithelial cells. This dissertation studied role of ciliated cells during repair of the respiratory epithelium following acute lung injury. Ciliated cells, previously considered terminally differentiated, underwent squamous cell metaplasia within 12-24 hours after bronchiolar injury caused by naphthalene. Dynamic changes in cell shape and gene expression accompanied the transition from squamous to cuboidal to columnar cell types as differentiation-specific cell markers were restored. Transcription programs critical for lung morphogenesis and differentiation, involving TTF-1, Foxa2, Foxj1, β-catenin and Sox proteins (Sox17 and Sox2) were utilized during repair of the bronchiolar epithelium. Similar dynamic changes in the expression of these transcription factors occurred in ciliated and Clara cells during regeneration of the lung following unilateral pneumonectomy. These findings supported the concept that ciliated cells have remarkable plasticity and serve as a source of progenitor cells for the respiratory epithelium following lung injury. Sox17 in respiratory epithelial cells was first detected in the fetal lung at embryonic day 18 and, thereafter, was restricted to ciliated cells. Conditional expression of Sox17 in the epithelial cells of embryonic lung inhibited peripheral epithelial cell differentiation, disrupted branching morphogenesis and promoted proximal cell fate. Conditional expression of Sox17 in peripheral respiratory epithelial cells of adult lung induced hyperplastic clusters of cells expressing markers of multiple proximal respiratory epithelial cell types. The present findings support the concept that Sox17 activates progenitor cell behavior of respiratory epithelial cells in adult lung and may be involved in maintenance of ciliated cell characteristics by influencing gene expression during development.
|School:||University of Cincinnati|
|Department:||Molecular and Developmental Biology|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/10(E), Dissertation Abstracts International|
|Keywords:||Epithelium, Repair, Respiratory|
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