In many organ systems, cells projecting hundreds of beating cilia, called multiciliate cells, produce a vigorous fluid flow that transports biological materials along luminal surfaces. Multiciliate cells populate the respiratory airways, the reproductive tract, and the ventricles of the brain, where the flow they produce has significant implications for human health. A key process in achieving directed flow is to align beating cilia along a common planar axis, requiring mechanisms that orient the rotational axis of the basal body at the base of each cilium. This process is known to be initiated by the planar cell polarity pathway, and to involve flow-based cues and elements of the cytoskeleton, but the mechanisms that align cilia direction are largely unknown. To address this issue, one approach is define the genetic pathways that drive the differentiation of multiciliate cells, and to use these pathways to identify novel factors that underlie cilia orientation. Specifically, this approach addresses the fact that the basal bodies in a multiciliate cell are highly specialized compared to those found in other ciliated cells, but the molecular bases of these specialization remain undefined. Using this approach, basal body factors involved in cilia orientation will be identified, and their role in producing directed fluid flow will be characterized. The factors studied include a new basal body associated protein required for maturating cilia orientation, proteins that comprise a basal body appendage called the ciliary rootlet, and candidate proteins that have been identified based on their structural features, and the fact that their expression is associated with multiciliate cell differentiation. The proposed studies will generate new insights into the cell specific components that allow basal bodies in multiciliate cells to mediate directed fluid flow, and lay the foundation for understanding how flow can fail in human diseases such as primary ciliary dyskinesia.
Multiciliate cells play important roles in human health by generating fluid flow in the brain, lung and reproductive tract, but the mechanisms that enable these cells to orient their beating cilia are poorly understood. To study these mechanisms, the proposed research will focus on new components of the basal body required for cilia orientation, including a family of poorly characterized coiled-coil proteins. Results from these studies will ai in the understanding of human diseases that affect ciliated epithelia, such as the ciliary defects that occurs in primary ciliary dyskinesia and Kartagener's syndrome.
|Walentek, Peter; Quigley, Ian K; Sun, Dingyuan I et al. (2016) Ciliary transcription factors and miRNAs precisely regulate Cp110 levels required for ciliary adhesions and ciliogenesis. Elife 5:|
|Chien, Yuan-Hung; Keller, Ray; Kintner, Chris et al. (2015) Mechanical strain determines the axis of planar polarity in ciliated epithelia. Curr Biol 25:2774-84|
|Chien, Yuan-Hung; Werner, Michael E; Stubbs, Jennifer et al. (2013) Bbof1 is required to maintain cilia orientation. Development 140:3468-77|
|Quigley, Ian K; Stubbs, Jennifer L; Kintner, Chris (2011) Specification of ion transport cells in the Xenopus larval skin. Development 138:705-14|
|Antic, Dragana; Stubbs, Jennifer L; Suyama, Kaye et al. (2010) Planar cell polarity enables posterior localization of nodal cilia and left-right axis determination during mouse and Xenopus embryogenesis. PLoS One 5:e8999|
|Mitchell, Brian; Stubbs, Jennifer L; Huisman, Fawn et al. (2009) The PCP pathway instructs the planar orientation of ciliated cells in the Xenopus larval skin. Curr Biol 19:924-9|
|Park, Tae Joo; Mitchell, Brian J; Abitua, Philip B et al. (2008) Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells. Nat Genet 40:871-9|
|Stubbs, Jennifer L; Oishi, Isao; Izpisua Belmonte, Juan Carlos et al. (2008) The forkhead protein Foxj1 specifies node-like cilia in Xenopus and zebrafish embryos. Nat Genet 40:1454-60|
|Marshall, Wallace F; Kintner, Christopher (2008) Cilia orientation and the fluid mechanics of development. Curr Opin Cell Biol 20:48-52|