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RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis

ABSTRACT: A core pathophysiology underlying many respiratory diseases is multiciliated cell dysfunction leading to inadequate mucociliary clearance. Due to the prevalence and high variability of etiologies of MCC dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelium, however this does not apply to all cell types nor occur evenly across all cells in the same cell population. In this study we investigated we further investigate how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells we identify RBL2 as an inhibitor of the transcriptional activity of Multicilin. Both knockdown of RBL2 and phosphorylation of RBL2 driven by exposure to an air-liquid interface in the presence of Multicilin activated multiciliogenesis demonstrating a dynamic interaction regulating the differentiation of human airway epithelial cells. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases where mucociliary clearance is impeded.

ORGANISM(S): Mus musculus

PROVIDER: GSE235682 | GEO | 2024/01/31

REPOSITORIES: GEO

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Project description:Study Smoking and COPD are associated with decreased mucociliary clearance and healthy smokers have shorter cilia in the large airway than nonsmokers. Intraflagellar transport (IFT) is the process by which cilia are produced and maintained. We assessed expression of IFT-related genes in smokers and nonsmokers and evaluated cilia length in the large and small airway of nonsmokers, healthy smokers, and smokers with COPD. Methods Airway epithelium was obtained via bronchoscopic brushing. Affymetrix microarrays were used to evaluate IFT gene expression in 2 independent data sets from large and small airway. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject. Results All 40 IFT genes were expressed in the human large and small airway epithelium. In the large airway, 10 IFT genes were down-regulated and 1 up-regulated in smokers. In the small airway, 11 genes were down-regulated and 3 up-regulated in smokers. A set of 8 IFT genes was down-regulated in both data sets. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. Answer to the Question These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking-induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies. Gene expression was assessed for 40 intraflagellar transport related genes in the LAE of nonsmokers (n=21) and healthy smokers (n=31) and the SAE of an independent group of nonsmokers (n=28) and healthy smokers (n=69). Cilia length was assessed in a total of 228 airway epithelium samples, including 120 LAE samples and 108 SAE samples; a subset of the 228 samples is represented among the 149 samples in this Series.

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RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis

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