Building and shaping the apical extracellular matrix

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary Apical extracellular matrices (aECMs) are glycoprotein and lipid-rich layers that coat exposed surfaces of epithelia to protect them from pathogen infection and other environmental stresses. aECMs also shape and maintain integrity of apical domains (particularly those of narrow tubes) and can form elaborate body decorations. Understanding aECM biology is important because of the widespread roles that these matrices play in animal development and physiology, as well as in human health. Defects in aECMs contribute to medical conditions including deafness, lung disease, kidney disease, and vascular disease. A major challenge in the field has been the difficulty of visualizing these complex matrices, which are often damaged by histochemical fixation and not easily recapitulated within in vitro culture systems. This has hampered studies of how aECM components traffic to the apical domain, assemble at the proper time and place to execute their functions, form layers and three-dimensional substructures, and respond to genetic or environmental perturbations. Such questions can be addressed using a simpler model system. C. elegans has aECMs containing collagens, zona pellucida (ZP) domain proteins, proteoglycans, phospholipids, and other factors similar to those in mammalian ECMs, and it permits easy visualization of endogenous fluorescently-tagged aECM components in live animals, along with facile genetic manipulations. A better understanding of C. elegans aECM can inform the biology of conserved matrix protein families and what could be going wrong in human matrix-related diseases, while also informing design of methods to counter pathogenic nematodes. Important and broadly relevant questions addressed in this work include: 1) What controls aECM assembly at the proper time and place? 2) How are complex three-dimensional aECM structures formed and shaped? 3) What controls aECM protein secretion and endocytosis? 4) How does metabolism influence aECM? These questions will be addressed through genetic mutant analyses combined with light microscopy, electron microscopy, RNA expression profiling, and lipidomics experiments.