The RhoGAP HUM-7/Myo9 integrates signals to modulate RHO-1/RhoA during embryonic morphogenesis in Caenorhabditis elegans

During embryonic morphogenesis, cells and tissues undergo dramatic movements under the control of F-actin regulators. Our studies of epidermal cell migrations in developing C. elegans embryos have identified multiple plasma membrane signals that regulate the Rac GTPase, thus regulating WAVE and Arp2/3 complexes, to promote branched F-actin formation and polarized enrichment. We describe here a pathway that acts in parallel to Rac to transduce membrane signals to control epidermal F-actin through the GTPase RHO-1/RhoA. RHO-1 contributes to epidermal migrations through effects on underlying neuroblasts. We identify signals to regulate RHO-1-dependent events in the epidermis. HUM-7, the C. elegans homolog of human Myo9A and Myo9B, regulates F-actin dynamics during epidermal migrations. Genetics and biochemistry support that HUM-7 behaves as GAP for the RHO-1/RhoA and CDC-42 GTPases. Loss of HUM-7 enhances RHO-1-dependent epidermal cell behaviors. We identify SAX-3/ROBO as an upstream signal that contributes to attenuated RHO-1 activation through its regulation of HUM-7/Myo9. These studies identify a new role for RHO-1 during epidermal cell migrations, and suggest that RHO-1 activity is regulated by SAX-3/ROBO acting on the RhoGAP HUM-7.