The mucociliary epithelium holds a central position in both normal and pathological airway biology, as it provides both the interface for air exchange and the first line of defense against inhaled agents. Here, we will study the transcription factor RFX2, which we have shown is essential for two crucial aspects of mucociliary epithelial development and maturation. 1) Our preliminary data demonstrate an essential role for RFX2 in motile ciliogenesis. We will combine a novel model system, in vivo imaging, and a unique suite of genomic and bioinformatic approaches to study the role of RFX2 in the multi-ciliated cells. 2) Newly-born multi-ciliated cells arise from basally-located mesenchymal stem cells that must migrate apically and insert into the epithelium. This crucial process in mucociliary biology remains almost totally undefined, but we find that RFX2 is essential for this insertion. We will again combine genomics, bioinformatics and in vivo imaging to study the role of RFX2 in this context. By rapidly determining the functions of several new genes involved in distinct processes in mucociliary epithelial development, the aims in this project will provide critical new depth to our understanding of these essential tissues. Moreover, by linking a single transcription factor to the control of two such disparate aspects of mucociliary epithelial biology, the experiments here will add crucial new breadth to our understanding as well. Impact: Experiments proposed here will lead to a more detailed understanding of the cell biology and genetics of mucociliary epithelia. The results will aid in the development of regenerative therapies aimed at repairing or restoring damaged tissue and improving mucus clearance in patients with airway disease.

Public Health Relevance

The airway is lined by a fascinating tissue called the mucociliary epithelium. The key feature of this tissue is to promote exchange of gases (oxygen and carbon dioxide) between the air and the blood, but another critical function of this tissue is performed by two key cell types, one that secretes mucus and the other decorated by tiny motile projections called cilia. The mucus forms a layer of disposable protection against inhaled particles and germs, while the cilia keep the mucus moving, replacing the old with new. Airway diseases such as asthma and COPD are exacerbated by defects (either congenital or induced) in the function of this mucociliary system. We propose here to use a battery of diverse approaches (novel animal models, genetic manipulations, time-lapse movies, large-scale 'genomic' analysis, and computational biology) to accelerate the understanding of the development of mucociliary epithelia. The results will aid in the development of regenerative therapies aimed at repairing or restoring damaged tissue and improving mucus clearance in patients with airway disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Postow, Lisa
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University of Texas Austin
Schools of Arts and Sciences
United States
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Tu, Fan; Sedzinski, Jakub; Ma, Yun et al. (2018) Protein localization screening in vivo reveals novel regulators of multiciliated cell development and function. J Cell Sci 131:
Butler, Mitchell T; Wallingford, John B (2017) Planar cell polarity in development and disease. Nat Rev Mol Cell Biol 18:375-388
Sigg, Monika Abedin; Menchen, Tabea; Lee, Chanjae et al. (2017) Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. Dev Cell 43:744-762.e11
Drew, Kevin; Lee, Chanjae; Huizar, Ryan L et al. (2017) Integration of over 9,000 mass spectrometry experiments builds a global map of human protein complexes. Mol Syst Biol 13:932
Adler, Paul N; Wallingford, John B (2017) From Planar Cell Polarity to Ciliogenesis and Back: The Curious Tale of the PPE and CPLANE proteins. Trends Cell Biol 27:379-390
Sedzinski, Jakub; Hannezo, Edouard; Tu, Fan et al. (2017) RhoA regulates actin network dynamics during apical surface emergence in multiciliated epithelial cells. J Cell Sci 130:420-428
Wallmeier, Julia; Shiratori, Hidetaka; Dougherty, Gerard W et al. (2016) TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization. Am J Hum Genet 99:460-9
Toriyama, Michinori; Lee, Chanjae; Taylor, S Paige et al. (2016) The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nat Genet 48:648-56
Sedzinski, Jakub; Hannezo, Edouard; Tu, Fan et al. (2016) Emergence of an Apical Epithelial Cell Surface In Vivo. Dev Cell 36:24-35
Session, Adam M; Uno, Yoshinobu; Kwon, Taejoon et al. (2016) Genome evolution in the allotetraploid frog Xenopus laevis. Nature 538:336-343

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