Mechanotransduction in morphogenesis of mucociliary epithelium and multiciliated cells

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Abstract Every time we breathe, we inhale toxins and pathogens. The mucus produced in our airway traps these pathogens. Thousands of multiciliated cells (multiple cilia per cell, MCCs) line the epithelium of our airway work in a synchronized fashion to propel the mucus upwards and out of our body. This coordinated process is known as mucociliary clearance, which prevents pathogens from moving to our lungs and causing irreparable damage. Despite the central role MCCs play in mucociliary clearance, our understanding of the morphogenesis of MCCs in the context of mucociliary epithelium remains incomplete. For example, the assembly of too many or too few cilia is associated with impaired MCC function and can lead to pathological outcomes. However, the mechanisms that define the cilia number remain unaddressed. Using an in vivo model of Xenopus embryonic epidermal MCCs, we recently discovered that the centriole number depends on the apical area of the cell. Moreover, we demonstrated that mechanical tension that affects the apical area of MCCs also calibrates centriole number via mechanosensitive (MS) ion channel Piezo1. Our results have raised many important questions about the mechanisms of Piezo1 function in MCCs. Also, they strongly suggested that mechanotransduction plays a central role in the morphogenesis of mucociliary epithelia, specifically MCCs. This proposal will focus on elucidating the role of mechanical forces and mechanotransduction pathways in determining the centriole number and apical area of MCCs and non-MCCs using three complementary approaches. First, we will take a gene-specific approach to examine the role of Piezo1 in centriole number control. Second, we will take a cellular biomechanics approach to understand the interaction between tissue- scale and cell-intrinsic forces in determining the apical area of MCCs and non-MCCs. Third, we will use a systems approach to identify other MS genes involved in MCC morphogenesis. Our long-term goal is to elucidate the mechanisms that define the properties of individual organelles (e.g., size and number of cilia) and how they relate to the architecture of cells (e.g., apical size, cilia organization) and the mucociliary tissue (arrangement of MCCs and non-MCCs) to generate efficient fluid flow.