Defining the mechanisms that remodel the multivalent domain structures of cell junctions during morphogenetic activities
Developmental Biology
Final Report Abstract
Adherens junctions (AJs) are responsible for the integrity of tissues as they ensure proper cellcell connections but also tension sensing and communication via the cytoskeleton. Malfunction of those characteristics can lead to metastasis of cancer cells, diseases, and perturbations during embryonal development. For this reason, the understanding of AJ formation, integrity and function is crucial. The core components of AJ are comprised of E-Cadherin, that spans the cell membrane and connects to the extracellular part of E-Cadherin of neighboring cells as well as to the cytoskeleton at the inside of the cell. However, several proteins ensure and reinforce that connection when cells are under tension or when they change their shape or divide. In my work, I propose that these proteins do not act in a simple upstream-downstream pathway but as reinforcing nodes of a network which changes over time and space. I investigated the role of Polycheatoid (Pyd) within this network in embryos of the fruit fly Drosophila melanogaster, in which AJ proteins and structure are highly conserved. The vertebrate ortholog of Pyd, ZO-2, is known to regulate junction tension, localization of other junction associated proteins and F-actin turnover. In my work I found that Pyd localizes in a broad and cloudlike fashion at and around AJs. This localization could be a hint for phase separation which is also emphasized by the sequence information of the protein, containing long disordered regions. Furthermore, I found that Pyd supports junction dynamics during the developmental process of germband extension. Embryos mutant for pyd have slower junction dynamics and reduced junctional tension. Furthermore, I found that junctional planar polarized proteins are hyper polarized in pyd mutants. These findings lead to the assumption that Pyd functions in reinforcement of the AJ-cytoskeleton connection. Interestingly, the function of Pyd is dispensable for the localization of other junction-associated proteins to AJs. However, it is possible that Pyd acts in stabilizing those proteins at the junction maybe due to its phase separation ability. Interestingly, the overexpression of Pyd led to several phenotypes including ectopic furrows and developmental defects. This could hint to a balancing function of Pyd in which not enough or too much Pyd could lead to malfunction of the junction-cytoskeleton balance. Overall, my work led to better understanding of the AJ-cytoskeleton connection and the role of Pyd in this system.
Publications
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Scribble and Dlg organize a protection racket to ensure apical–basal polarity. Proceedings of the National Academy of Sciences, 117(24), 13188-13190.
Schmidt, Anja & Peifer, Mark
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Polychaetoid/ZO-1 strengthens cell junctions under tension while localizing differently than core adherens junction proteins. Molecular Biology of the Cell, 34(8).
Peifer, Mark; Schmidt, Anja; Finegan, Tara; Häring, Matthias; Kong, Deqing; Fletcher, Alexander G.; Alam, Zuhayr; Grosshans, Jörg & Wolf, Fred
