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Sox2 is a Master Regulator of Differentiation in Respiratory Epithelium

Tompkins, David H.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307985600

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
The most frequently amplified locus in human lung squamous cell carcinoma contains the gene for the transcription factor Sox2, yet the role of Sox2 in lung is unknown. The present study was undertaken to investigate the function of Sox2 in perinatal and adult lung. The central findings of this study are (a) Sox2 is necessary and sufficient for differentiation of Clara, ciliated, and goblet cells of the conducting airway epithelium, and (b) Sox2 is a positive regulator of proliferation in conducting airway epithelium. Previous studies have shown that Sox2 is critical for diverse biological processes, including maintenance and pluripotency of embryonic stem cells, morphogenesis of the trachea, esophagus, and eye, and development of differentiated cells in adult tongue, ear, and brain. In developing lung, Sox2 is present exclusively in cells lining the developing tubules (the future bronchioles). In mature lung, Sox2 is present in the epithelium of the conducting airways (bronchioles) and is absent from the epithelium of the gas-exchange compartment (alveoli). In the present study, perinatal knockout of the Sox2 gene specifically in the Clara cells of the mouse conducting airways resulted in an abnormal, low cuboidal epithelium with reduced proliferation and loss of the predominant differentiated conducting airway cell types (Clara and ciliated cells). Further, the Sox2-null bronchiolar epithelium was incapable of forming goblet cells during an allergen-challenge experiment, whereas Sox2-competent bronchiolar epithelium in control animals produced an abundance of goblet cells. Consistent with a role in differentiation, luciferase-reporter assays using immortalized human bronchiolar epithelial cells demonstrated Sox2 activation of the promoter region of differentiation marker genes (Clara cell Scgb1a1, Ciliated cell marker FoxJ1, Goblet cell marker Agr5). Sox2 inhibited a TGF-ß signaling assay in vitro and directly bound the TGF-ß signaling iii transducer SMAD3, defining a possible mechanism by which Sox2 contributes to increased proliferation. In vivo, transgenic Sox2 expression was induced in the Clara cells of the bronchiolar epithelium (where endogenous Sox2 was already present), and in the alveolar type II cells of the alveolar epithelium (where endogenous Sox2 was not present). Transgenic Sox2 expression in Clara cells induced a short term increase in proliferation and a loss of the Clara cell marker protein Scgb1a1. Transgenic Sox2 expression in alveolar type II cells led to a short-term increase in proliferation, and was sufficient to induce the dramatic, widespread appearance of abnormal alveolar cell clusters possessing well-formed ectopic cilia and marker proteins characteristic of bronchiolar Clara and ciliated cells. Taken together, these results support the following concepts: - In lung growth, homeostasis and allergen challenge, bronchiolar Clara cells differentiate into Clara, ciliated, and goblet cells in a process that requires Sox2. - Ectopic Sox2 expression in alveolar type II cells is sufficient to induce robust reprogramming of alveolar epithelium into bronchiolar epithelial-like cells. - Sox2 contributes to the positive regulation of proliferation in conducting airway epithelial cells.
Jeffrey Whitsett, MD (Committee Chair)
Nira Ben-Jonathan, PhD (Committee Member)
Jaroslaw Meller, PhD (Committee Member)
Susanne Wells, PhD (Committee Member)
James Wells, PhD (Committee Member)
Kathryn Wikenheiser-Brokamp, MDPhD (Committee Member)
163 p.
Biology
lung; transcription; differentiation; progenitor; stem

Recommended Citations

Citations

  • Tompkins, D. H. (2011). Sox2 is a Master Regulator of Differentiation in Respiratory Epithelium [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307985600

    APA Style (7th edition)

  • Tompkins, David. Sox2 is a Master Regulator of Differentiation in Respiratory Epithelium. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307985600.

    MLA Style (8th edition)

  • Tompkins, David. "Sox2 is a Master Regulator of Differentiation in Respiratory Epithelium." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1307985600

    Chicago Manual of Style (17th edition)

ucin1307985600
1,146
© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.