Sox2-Dependent Transcriptional Control Of Airway Differentiation In The Mouse Lung

Author

Belinda J. Hernandez, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

12-2014

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Dr. Jichao Chen

Committee Member

Dr. Richard Behringer

Committee Member

Dr. Elsa Flores

Committee Member

Dr. Nami McCarty

Committee Member

Dr. Eric Wagner

Abstract

The lung is a highly branched tree-like tubular system that results from more than 20 generations of the conducting airways and consists of 300 million alveoli for gas exchange. Airway branches form via branching morphogenesis and then mature into conducting airways, in which the number and distribution of different cell types need to be precisely controlled. The conducting airways contain four lung cell types: club cells, ciliated cells, basal cells, and neuroendocrine cells.SOX2 is a well-known conducting airway marker. SOX2 is a transcription factor that is known to be important in embryonic development and induction of pluripotent stem cells. We hypothesized that SOX2 controls cell differentiation in the conducting airways. To determine the role of SOX2 in the conducting airways, we used various mouse models to determine if SOX2 controls cell differentiation. SOX2 was deleted in the lung epithelium by using Sox2^EGFP/CKO and Shh^Cre/+. We observed a decrease in club cell, basal cell, and neuroendocrine cell differentiation when Sox2 is absent in the conducting airways. SOX2 overexpression was done by using Rosa26R-lox-stop-loxSox2(Gt(Rosa)26Sor^tm1/Sox2/blh) in the lung epithelium, Sox9 distal progenitor cells, alveolar type 1 cells, and alveolar type 2 cells. We found that SOX2 expression in the alveoli region reprograms alveoli cells into conducting airway cells. Mutant alveolar type 1 and type 2 cells expressing SOX2 are able to generate basal –like cells. Further, through microarray analysis we found SOX21, a transcription factor, significantly down regulated in the absence of Sox2. Sox21 has a unique expression pattern in the conducting airways. The expression of SOX21 is uniform in the proximal airways and sporadic in the distal airways. Together, these data suggest SOX2 controls cell differentiation in the conducting airways. Our data regarding how Sox2 controls airway cell differentiation in the mouse lung gives insight regarding direct differentiation from an immature cell to a specialize cell.

Keywords

SOX2, P63, Lung epithelium, conducting airway