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 and reproductive tracts, and the ventricles of the brain, and the flow they produce has significant implications for human health. Despite their importance, the developmental mechanisms that underlie the formation of these cells in diverse epithelia are still unknown. Specifically, multiciliate cell differentiation is likely to be under the control of a transcriptional code that is required for this cell type to form, but little is known about the nature of this code. To address this issue, the proposed experiments focus on a newly discovered gene, called Multicilin. Multicilin was identified in preliminary experiments based on its highly restricted expression in multiciliate cells in X. laevis embryos, but is also expressed in other organs that form multiciliate cells. In functional tests, Multicilin is required for multiciliate cells to form, and more remarkably will induce the formation of ectopic multiciliate cells when misexpressed in other regions of the embryo. Multicilin encodes a small protein with two domains required for function: a central coiled-coil domain similar to the one found in the cell cycle regulator, Geminin, and a second C-terminal domain required for transcriptional activity. Thus, the proposed experiments will determine whether Multicilin promotes the formation of multiciliate cells by both modulating cell cycle progression and by activating gene expression required for multiciliate cell differentiation. In addition, in order to induce multiciliate cell differentiation, Multicilin promotes the large-scale assembly of basal bodies required to anchor hundreds of cilia. By promoting novel pathways of centriole assembly that are unique to multiciliate cells, Multicilin can be exploited to gain insight into this poorly understood process. Thus, the results from the analysis of Multicilin will provide new information about the transcriptional and cell biological events that allow epithelial progenitors to turn into multiciliate cells. This information will likely speed progress in devising approaches to generate multiciliate cells from stem cells, either induced or embryonic, and for promoting the formation of multiciliate cells from other cell types during regeneration via transdifferentiation.
Multiciliate cells play important roles in human health by generating fluid flow in the brain, lung and reproductive tract, but the mechanisms that mediate the formation of these cells during embryogenesis are poorly understood. To study these mechanisms, the proposed research will focus on a new gene, called Multicilin, which is both necessary and sufficient to promote multiciliate cell formation. Analyzing Multicilin function will aid in the diagnosis and treatment of human disease that affect ciliated epithelia, such as the ciliary defects that occurs during primary ciliary dyskinesia and Kartegener's syndrome.
|Boon, Mieke; Wallmeier, Julia; Ma, Lina et al. (2014) MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Commun 5:4418|
|Wallmeier, Julia; Al-Mutairi, Dalal A; Chen, Chun-Ting et al. (2014) Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet 46:646-51|
|Ma, Lina; Quigley, Ian; Omran, Heymut et al. (2014) Multicilin drives centriole biogenesis via E2f proteins. Genes Dev 28:1461-71|
|Tan, Fraser E; Vladar, Eszter K; Ma, Lina et al. (2013) Myb promotes centriole amplification and later steps of the multiciliogenesis program. Development 140:4277-86|
|Stubbs, J L; Vladar, E K; Axelrod, J D et al. (2012) Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation. Nat Cell Biol 14:140-7|