Roles for YAP in multiciliogenesis

Boston University Medical Campus, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Cilia are thin hair-like projections that form on the surface of cells and help cells sense and respond to their environment. These structures are found ubiquitously throughout the body and defects cause a variety of diseases, collectively referred to as ciliopathies. In the lung, cilia are critical for defense of the epithelium against damage, and dysfunction of cilia ultimately leads to chronic respiratory disease. The aim of this proposed work is to determine the mechanism of cilia formation in the lung following cell fate specification, focusing on two proteins, Yes-associated protein (Yap) and Trim32. Classically described as a transcriptional effector of the Hippo pathway, Yap is recruited to the apical domain of ciliated cells at the base of cilia, and this proposal will explore a non-canonical role or Yap in regulating the cytoskeleton at that location. The requirement for Yap at different stages of cilia formation and maintenance will be determined through in vivo and in vitro assays using an inducible loss of function approach. We have identified Trim32, an E3 ubiquitin ligase that has been shown to target actin and has also been implicated in Bardet Beidl ciliopathies, as a Yap interacting protein. The activity of this protein and its requirement for Yap-directed ciliogenesis will be examined through gain and loss of function experiments in vitro. Collectively these studies will advance our understanding of cilia formation in the lung epithelium and improve our ability to combat ciliopathies and their detrimental impact on human health.