The mucociliary epithelium plays a key role in both normal and pathological airway biology, as it provides the first line of defense against inhaled agents. Defects in the structure or function of multiciliated cells (MCCs) in the mucociliary epithelium contribute to the progression of both genetic and acquired airway diseases. Here, we will study the molecular mechanisms controlling development and function of MCCs. 1) Our previous work demonstrated an essential role for the RFX2 transcription in motile ciliogenesis, and here we combine a novel model system, in vivo imaging, and a high-content screen for protein localization to ask how Rfx2 target genes govern actin assembly that in turn is crucial for ciliogenesis. 2) Our previous work has also generated a deeper appreciation of the complexity of molecular heterogeneity along the length of motile cilia. We will define the molecular hierarchy by which this heterogeneity is established and we link these mechanisms to cilia beating. 3) Dynein arms are complex multi-protein machines that drive ciliary beating and our protein localization screen suggests that the assembly process is compartmentalized in a novel, MCC-specific organelle. We will explore the molecular and cell biological mechanism underlying this novel organelle's function. By rapidly determining the functions of several new genes involved in distinct processes in mucociliary epithelial development, the Aims in this proposal will provide critical new depth to our understanding of these essential tissues. Moreover, by linking these 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

Motile cilia are small cellular projections that drive the movement of protective mucus in the airways, an essential element of healthy lung physiology. This proposal will explore the molecular and cell biology of motile cilia, thereby shedding light on the etiology of both genetic and acquired lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL117164-07
Application #
9891070
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Postow, Lisa
Project Start
2013-08-15
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78759
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:
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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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