PhD Discussions Sessions: Aida Garrido and Marina Uroz

Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches

Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities.

Traction forces at the cytokinetic ring regulate cell division and polyploidy in the migrating zebrafish epicardium

Epithelial repair and regeneration are driven by collective cell migration and division. Both cellular functions involve tightly controlled mechanical events. Mechanics of collective cell migration is increasingly well understood, but physical forces associated with cell division in cohesive epithelia have escaped experimental observation. Using the zebrafish epicardium as a model system, we show that cells dividing in a migrating epithelium exert large cell-extracellular matrix (ECM) forces during cytokinesis. These forces point towards the midbody and are exerted through paxillin-rich focal adhesions that connect the cytokinetic ring to the underlying extracellular matrix. Large forces at these adhesions are associated with failure of cytokinesis and polyploidy, indicating that abnormal cell-matrix adhesion at the cleavage furrow impedes the latest stages of abscission. Mechanical interaction between the cytokinetic ring and the ECM thus provide a new mechanism for the regulation of cell division and polyploidy.

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