Investigation of molecular mechanisms underlying polarization in developing neurons and migrating cells

Abstract

Cell polarity is a pivotal process in many cellular functions such as development, proliferation, and differentiation, and an aberrant polarization allows cells susceptible to various diseases. The molecular mechanisms underlying cell polarization have been studied in a wide range of mammalian organisms. However, mechanisms of how cells establish and maintain cell polarity are still fascinating questions. In chapter 1, we suggest the newly identified upstream cue of neuronal polarization during the developmental process. Using light-activated TrkB receptors, named “Opto-cytTrkB,” we found that local activation of TrkB receptors around the neurite end initiates actin waves, which have known to promote the competition between neurites to become a winning axon during the multipolar state. Furthermore, by concentrating actin waves in one specific neurite, we observed light-specific translocation of key axonal proteins to the Opto-cytTrkB-activated neurite. From these results, we suggest that local activation of Opto-cytTrkB switches the fate from minor to major axonal neurite during neuronal polarization by generating actin waves. In chapter 2, we investigated the new mechanisms for symmetry breaking in migrating fibroblasts. In order to migrate toward the one direction, cells need to accompany the confined actin polymerization and cdc42 activity, establishing the single front. Here, we defined FMNL2 and FMNL3, members of the formin family, as intrinsic mediators to facilitate the polarized cell morphology for persistent migration by restricting the actin polymerization and active cdc42 at the leading edge. In addition, we further investigate the mechanisms underlying the FMNL2 and -3-mediated cell polarization by observing their roles in microtubule arrangement and membrane trafficking along the microtubules.