Requirement and regulation of Rho GTPases during collective, in vivo border cell migration

Speaker

Jim Mondo
Molecular, Cellular, and Developmental Biology
UC Santa Barbara

Abstract

Cell migration is a fascinating and complex process that is required for development, wound healing, and immune system function. Fundamentally, cells migrate using characteristic features, including extension of protrusions coupled with adherence to a substrate at the front, and contraction and release at the rear. This dynamic process is regulated by actomyosin dynamics, which are controlled in part by the Rho family of small GTPases. Rho GTPase activity is precisely temporally and spatially localized during cell migration, largely via activation by Rho family Guanine Exchange Factors (GEFs) and inhibition by GTPase Activating Proteins (GAPs).

Foundational research in the field of cell migration focused on the movement of single cells in vitro on petri dishes coated with a variety of matrices. However, physiological migrations often take place with cells moving as collectives, either as sheets, strands or clusters. Collective cell migration drives many disease states, including cancer metastasis as cells leave the primary tumor to invade the surrounding tissue. Recent research has shown that clusters of heterogeneous cells are up to 100 fold more efficient at generating new tumors than single cells alone.

I study collective cell migration within an in vivo environment using the border cell cluster found in the Drosophila ovary. Using the border cells as a model of collective motility, I first documented the spatial and temporal activity domains of Rho family GTPases across the border cell cluster using optogenetic tools and biosensors. I then turned my attention to how Rho family GEFs and GAPs mediate Rho GTPase activity by performing a comprehensive screen of all Drosophila GEFs and GAPs to test their requirement for border cell migration. From this screen I was able to classify genes by their ability to regulate cluster morphology, protrusion dynamics and ability to regulate specific GTPases. My dissertation proposes a network of GEF/GAP interactions and regulatory targets required for collective cell migration.