Mechanisms of protein patterning on the membrane and inside the cell
Many cellular and developmental processes rely on the precise positioning of proteins to ensure proper morphogenesis. In early developing sea star oocytes, the symmetry breaking and meiosis processes require robust coupling between the spatiotemporal dynamics of developmental signaling (Wnt pathway proteins Dishevelled), cell-cycle dependent kinase (such as Cdk1), cytoskeletal signaling proteins (Rho kinase) and cell shape dynamics. During my PhD, I combined live cell imaging, advanced computational pipelines and theoretical modeling to elucidate the mechanisms of protein pattern formation and its coupling to cell shape. With micropatterning techniques, we discovered that cell shape information encoded in a cytosolic gradient can be decoded by a bistable front of a RhoA regulator. In turn, this bistable front precisely positions RhoA by locally triggering excitable dynamics. We posit that this hierarchical coupling between a biochemical (Cdk1) gradient and protein (Rho) self-organization provides mechanochemical feedback for cell shape sensing and control in early oocyte and embryo development.
Further, in a separate project, we found that the excitable Rho dynamics on the membrane exhibit spiral wave dynamics. Using phase and topological analysis, we showed that the membrane Rho spiral wave dynamics can be understood as interactions between topological defects in the phase field, analogous to the roles of topological defects during tissue morphogenesis. These tools could be extended to the study of excitable spiral dynamics in neuronal systems and cardiac arrhythmia. In another collaboration, we studied how polarized Dishevelled dissolves and reassembles during meiosis, highlighting how maternal cues and endosome association drive Dishevelled localization and embryonic axis specification in sea star oocytes. Altogether, these works demonstrate how experimentally-constrained mathematical models can reveal mechanisms of protein pattern formation fundamental in cellular morphogenesis during development.
Tan TH*, Liu J*, Miller PW*, Tekant M, Dunkel J, and Fakhri N, (2020) “Topological turbulence in the membrane of a living cell.” Nature Physics. [PDF] | See also: Nature Physics cover art | MIT news | phys.org | physicsworld.com | Research highlight in Nature
Wigbers M*, Tan TH*, Brauns F, Jinghui L, Swartz Z, Frey E, Fakhri N (2021) “A hierarchy of protein patterns robustly decodes cell shape information.” Nature Physics.