Chibby and Wnt Signaling in Ciliated Cell Differentiation

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DESCRIPTION (provided by applicant): Motile cilia are abundant in our respiratory tract, and beat synchronously in waves to propel inhaled debris and pathogens entrapped in mucus to the pharynx. This provides an important innate defense mechanism against respiratory infections. Motile cilia are usually found as clusters of 100 to 300 on the apical surface of a ciliated cell in the respiratory epithelium. Dysfunction of motile cilia has been linked to human diseases, especially primary ciliary dyskinesia (PCD). Despite their clinical importance, little is known about the key molecules and signaling pathways that govern motile ciliogenesis and ciliated cell differentiation. Therefore, understanding these fundamental biological phenomena is crucial for developing novel therapeutic strategies for the prevention and treatment of PCD and other cilia-related disorders. Chibby (Cby) was originally isolated as an evolutionarily conserved antagonist of the Wnt/¿-catenin signaling pathway. Cby physically interacts with the pivotal downstream coactivator ¿-catenin and inhibits ¿-catenin-mediated transcriptional activation. Intriguingly, Cby-knockout (Cby-/-) mice suffer from recurrent respiratory infections due to a complete absence of mucociliary transport activity, reminiscent of PCD. Our studies further revealed that ciliated cells in the nasal and lung epithelia of Cby-/- mice are poorly differentiated characterized by a markedly decreased number of motile cilia. Consistent with this phenotype, we found that endogenous Cby protein localizes to the base of cilia. Our findings therefore establish that Cby plays an essential role in proper formation/function of motile cilia in the respiratory tract. However, the cellular and molecular bases underlying the ciliary defects of Cby-/- mice remain largely unexplored. In addition, whether the ciliogenic function of Cby relates to Wnt/¿-catenin signaling is unclear. The goal of this proposal is to elucidate the roles of Cby, Cby-interacting proteins and Wnt/ ¿-catenin signaling in motile ciliogenesis and tracheal ciliated cell differentiation. In order to achieve this goal, we propose the following Specific Aims: Specific Aim 1. Investigate the role of Cby in tracheal ciliated cell differentiation; Specific Aim 2. Examine transcriptional regulation of the Cby gene during differentiation of tracheal ciliated cells; Specific Aim 3. Isolate Cby-binding partners and define their roles in ciliated cell differentiation. We expect that these experiments will contribute to a fundamental understanding of the molecular and cellular mechanisms of ciliogenesis and ciliated cell differentiation. PUBLIC HEALTH RELEVANCE: Motile cilia (tiny hair-like projections from ciliated cells) lining our respiratory tract wave back and forth to effectively remove inhaled debris and microorganisms entrapped in mucus, and human patients with dysfunctional cilia suffer from recurrent respiratory infections, leading to respiratory insufficiency. Therefore, understanding mechanisms of motile cilia formation and ciliated cell differentiation is critical for development of new therapies for diseases caused by dysfunctional cilia. Our research investigates roles of Chibby protein and Wnt signaling pathway in motile cilia formation and ciliated cell differentiation, and will most likely contribute to our better understanding of these important biological processes.