Exocyst is involved in polarized cell migration and cerebral cortical development

Abstract

Neuronal migration is essential for proper development of the cerebral cortex. As a first step, a postmitotic cell extends its leading process, presumably by adding new membrane at the growing tip, which would enable directed locomotion. The goal of the present study was to determine if biosynthetic exocytic pathway is polarized in migrating cells and whether polarized exocytosis promotes directed cell migration. A promising candidate for controlling the spatial sites of vesicle tethering and fusion at the plasma membrane is a protein complex called the exocyst. We found that cell migration in a wound assay, as well as cortical neuronal migration during embryonic development was impaired when the exocyst was disturbed. By combining TIRF microscopy and a stochastic model of exocytosis, we found that vesicle exocytosis is preferentially distributed close to the leading edge of polarized cells, that the exocytic process is organized into hotspots, and that the polarized delivery of vesicles and their clustering in hotspots depend on the intact exocyst complex. The exocyst complex seems to achieve this spatial regulation by determining the sites at the membrane where secretory vesicles tether. Thus, our study supports the notion that polarized membrane traffic regulated by the exocyst is an essential component of cell migration and that its deficit may lead to cortical abnormalities involving cortical neuronal malpositioning.astrocyte ͉ cell polarization ͉ membrane trafficking ͉ neuronal ectopia ͉ neuronal migration

A novel high-content analysis tool reveals Rab8-driven cytoskeletal reorganization through Rho GTPases, calpain and MT1-MMP

“…Alternatively, because the Sec15p subunit of the exocyst is an effector of the yeast Rab8 homolog (Guo et al, 1999), the exocyst might well provide a local cue to promote vesicle tethering by interacting with Rab8-decorated vesicles. Accordingly, it has been implicated in directional cell migration, actin polymerization and delivery of MT1-MMP to the plasma membrane (Letinic et al, 2009;Liu et al, 2009;Monteiro et al, 2013;Sakurai-Yageta et al, 2008;Spiczka and Yeaman, 2008). Taken together, our results support the hypothesis that Rab8 acts as a plasma membrane hub converging secretory and recycling trafficking routes through Rab6-, and Rab11-and Rabin8-dependent mechanisms, respectively.…”

RalA promotes a direct exocyst-Par6 interaction to regulate polarity in neuronal development

“…RalA and the exocyst are involved in neuronal migration in the developing neocortex (Letinic et al, 2009;Jossin and Cooper, 2011). At the molecular level, however, the consequence of RalA-exocyst interaction is still unclear.…”

PIP kinases define PI4,5P2 signaling specificity by association with effectors

“…The exocyst complex is a multiprotein complex essential for polarized delivery and tethering of secretory vesicles to specific domains of the plasma membrane for secretion [142]. This complex is thought to function prior to SNARE-mediated vesicle fusion with the plasma membrane [142].…”