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A Transgenic FOXJ1-Cre System for Gene Inactivation in Ciliated Epithelial Cells

Department of Medicine and Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri

Correspondence and requests for reprints should be addressed to Michael J. Holtzman, Washington University School of Medicine, Pulmonary and Critical Care Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110-1093. E-mail: holtzman{at}im.wustl.edu

Ciliated airway epithelial cells are critical for mucosal barrier function, including host defense against pathogens. This cell population is often the primary target and thereby the first line of defense against many common respiratory viruses. It is also the precursor for mucous cells and thereby promotes mucociliary clearance of infectious and other noxious agents. Cells with motile cilia in other organs (e.g., brain and reproductive organs) may also have roles in development and reproduction. However, definitive proof of ciliated cell function is hampered by the lack of strategies to specifically target this cell population for loss of function in vivo. To this end, cell type–specific gene promoters have been combined with the Cre/LoxP system to disrupt genes in airway and alveolar epithelial cell populations expressing surfactant protein C (SP-C) or Clara cell secretory protein (CCSP). By contrast, an analogous system to disrupt gene function in ciliated airway epithelial cells was still needed. Here we report the generation and analysis of mouse lines with a FOXJ1 promoter driving the Cre recombinase and show that this system mediates genomic recombination specifically in ciliated cells. The pattern of recombination recapitulates endogenous FOXJ1 promoter function, being restricted to ciliated cells present in pulmonary airways as well as choroid plexus, ependyma, oviduct, and testis. This transgenic mouse system thereby offers a new strategy for specific knockouts of genes in ciliated cells. It should prove extremely useful for defining ciliated cell function in airway mucosal immunity as well as development and reproduction.

Key Words: pulmonary airways • mucosal immunity • FOXJ1 transcription factor • cell-specific gene knockouts • Cre/LoxP system

CLINICAL RELEVANCE We developed a new tool for defining the role of ciliated epithelial cells in disease. For example, the system could be used to block respiratory viral infection by down-regulating a gene that allowed virus to bind to ciliated airway epithelial cells.

 

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