Multi-modal Atlas of Self-organized Mucociliary Patterning

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Tissues are composed of multiple cell types that must be kept in balance and arranged in stereotyped patterns for the emergence of physiological organ function. In development, homeostasis and regeneration, such precise choreography depends on self-organized mechanisms that integrate cell fate choices, controlled by gene regulatory networks, and cell-/tissue-level morphogenetic movements. This is inherently difficult to study in internal organs, e.g. the airway epithelium. The embryonic Xenopus epidermis serves as an excellent paradigm to uncover conserved principles of vertebrate mucociliary tissue patterning. At steady-state, the epidermis is composed of two cell layers, a basal layer of stem cells, and a superficial epithelial layer containing secretory cells, which regulate ion homeostasis, produce mucus and antimicrobial peptides, and evenly spaced multiciliated cells forming >100 motile cilia that beat synchronously and produce extracellular fluid flow to remove mucus and pathogens – a process called mucociliary clearance. The precise cell type proportions are variably adapted in different regions of the epidermis, and we postulate that this is to optimize organismal mucociliary function. In the MAP project, we wish to bring this model to the next level by combining systems and single cell transcriptomics with live cell imaging to identify the entire complement of cell types and cell behaviors necessary to build the mature mucociliary epidermis. We aim to determine the molecular mechanisms that are used to generate and adapt mucociliary cell type composition/organization in the embryonic epidermis by analyzing both signaling and morphogenetic contributions to pattern formation. Specifically, we will: (1.) Establish a detailed morphological, transcriptomic and molecular map of mucociliary cell types over the entire embryo. (2.) Use new fluorescent reporters to study the behavior of all mucociliary cell types by live cell imaging. (3.) Address the role of the Scf/Kit adhesion/repulsion system in generating variable distributions of ciliated and secretory cells. (4.) Elucidate the functional role of signaling on final mucociliary tissue patterning by combining mathematical models and experimental manipulations, during specification and in trans-differentiation. The ambitious goals of this project will be reached through the association of the Walentek and Kodjabachian labs, which hold great expertise in Xenopus systems biology, signaling studies and live imaging. This project will allow us to investigate tissue-wide patterning with unprecedented spatiotemporal resolution, and elucidate conserved principles of pattern formation in vertebrate tissue development. Gaining a better understanding of the mechanisms that regulate mucociliary cell type composition in vivo will form the basis to understand physiological adaptations and to eventually improve diagnosis and treatment of airway diseases.