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Abstract

Epithelia undergo morphogenetic remodeling events to generate the embryo’s final form. Morphogenetic episodes may arise from relatively small, discrete changes in cellular behaviors, namely cell migration, constriction, intercalation, division, and extrusion events. These highly conserved behaviors arise from the spatial and temporal integration of cytoskeletal-based contractile forces at adhesion complexes, the tuning of which can either maintain tissue homeostasis or allow for dynamical tissue processes. This mechanochemical signaling therefore underlies mechanical force transmission and transduction necessary for proper cell and tissue mechanics. Failure in the strict regulation of this mechanochemical circuitry can result in aberrant cellular and tissue behaviors, producing various birth defects and cancers. As embryogenesis is highly complex in nature, reductionist approaches have become increasingly appealing and tractable to shed light on conserved morphogenetic mechanisms. The work described here takes a bottom-up approach to elucidate the complex behaviors described in development. Specifically, to examine cell shape maintenance and cell-cell junction length regulation via the cytoskeletal regulator and small GTPase, RhoA. RhoA is highly dynamic during morphogenesis and exhibits complex behaviors that are thought to generate asymmetric, ratcheted junction length changes. However, little is known about RhoA regulation in determining junction length and contractile phenotypes. Here, I use optogenetic probes and various pharmacological compounds to exogenously regulate RhoA at cell-cell junctions, elucidating what is necessary and sufficient to drive cell shape changes in model epithelia. I couple this work with a collaboration in mathematical modeling to further elucidate the mechanisms by which RhoA confers junction length. Together, we find that junction deformation contains a strain threshold to dictate junction length and that the duration, strength, and temporal sequence of RhoA-mediated contractility confers length. Junction stabilization at shorter lengths requires endocytosis to remove junctional and membrane material for progressive shortening. I additionally find that, during contraction, junction shortening occurs asymmetrically with one motile vertex and one less-motile vertex. This vertex motion is dependent on the feedback between RhoA and E-Cadherin, which produces an opposing frictional force to limit junctional contractions. The work described here begins to uncover the biophysical and cellular basis of RhoA regulation in junction mechanics, providing exciting new hypotheses to test how RhoA-mediated mechanical forces drive junction length changes.

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