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THE ROLE OF THE ETS TRANSCRIPTION FACTOR Elf5 IN LUNG DEVELOPMENT

METZGER, DAVID EDWARD

Abstract Details

2007, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
Epithelial FGF signaling during lung organogenesis has been shown to be essential for branching morphogenesis, specification of surfactant producing type II cells and the maintenance of epithelial progenitors. In order to determine epithelial targets of FGF signaling, E11.5 mouse lungs were cultured for 24 hours in the presence of the FGF receptor antagonist SU5402, which inhibited branching morphogenesis. Affymetrix gene chip analysis identified a number of epithelial genes regulated by FGF signaling, including Elf5, a member of the Epithelial Specific Ets family of transcription factors. In situ hybridization revealed that Elf5 had a dynamic pattern of expression during lung development, transitioning from the distal epithelium at E11.5 to the proximal airway epithelium in late lung development. It was also determined that expression of Elf5 was induced by FGF7 and FGF10, ligands of epithelial specific FGFR2b. In order to further define the pathways by which FGFs activate Elf5 expression, E11.5 lung tips were also cultured in the presence of inhibitors of PI3-Kinase/Akt-mediated signaling (LY294002) and MAP Kinase/Erk-mediated signaling (U0126). It was found that LY294002 significantly reduced Elf5 expression, whereas U0126 had no effect. The observation that proximal airway epithelium (a tissue that lacks expression of distal epithelial markers) highly expressed Elf5 in late gestation suggested that Elf5 may play a role in negatively regulating distal epithelial specification/differentiation. To test this hypothesis, a transgenic mouse model was generated containing a doxycycline inducible HA-tagged Elf5 transgene under the control of the lung epithelium specific Sftpc promoter to overexpress Elf5 in the distal lung epithelium. The results indicated that high Elf5 expression disrupted branching morphogenesis and negatively regulated distal epithelial differentiation of the lung epithelium while repressing type II cell enriched genes Erm, Napsin and Sftpc. Furthermore, microarray analysis of Elf5 overexpressing lungs revealed that while repressing some genes normally present in differentiated type II cells, high Elf5 expression also induced the expressions of other genes present in type II cells, suggesting that appropriate levels of Elf5 expression must be regulated for the proper specification and the subsequent differentiation of type II cells. Further analysis of the microarray results indicated that Elf5 overexpression induced the ectopic expressions of genes not normally associated with the lung. These results suggest that high Elf5 expression in the lung epithelium plays a role in negatively regulating the specification and differentiation of type II cells but may also play a role in keeping the lung epithelium somewhat pluripotent.
Dr. John Shannon (Advisor)
200 p.

Recommended Citations

Citations

  • METZGER, D. E. (2007). THE ROLE OF THE ETS TRANSCRIPTION FACTOR Elf5 IN LUNG DEVELOPMENT [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1197664589

    APA Style (7th edition)

  • METZGER, DAVID. THE ROLE OF THE ETS TRANSCRIPTION FACTOR Elf5 IN LUNG DEVELOPMENT. 2007. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1197664589.

    MLA Style (8th edition)

  • METZGER, DAVID. "THE ROLE OF THE ETS TRANSCRIPTION FACTOR Elf5 IN LUNG DEVELOPMENT." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1197664589

    Chicago Manual of Style (17th edition)