Coordinated Regulation Of Cofilin Asymmetry And Phosphorylation Promotes Guided Cell Migration In Morphogenesis

Cell migration is a fundamental process in many physiological and pathological events, including embryogenesis, immune responses, wound healing, and cancer-cell metastasis. During Drosophila oogenesis, two actin dynamics regulators, cofilin and Rac are required for a chemotactic and tumor-like migration of a coherent cluster of cells called border cells. Cell culture data showed Rac and cofilin are both essential for lamellipodium formation. But the perplexing fact is Rac signaling results in phosphorylation and hence inactivation of cofilin in vitro.In this study, we genetically probe the relationship between Rac and cofilin in vivo during Drosophila border cell migration, a well-established and genetically tractable migration system. We show here that cofilin is required for lamellipodial protrusion and its activity promotes the number and length of protrusions in the border cell cluster. Interestingly, reducing the dosage of cofilin by half or expressing a dominant negative mutant form S3E can effectively rescue the migration and protrusion defects exhibited by Rac-deficient border cells. Moreover, we observed that cofilin has a moderate localization in the migratory front of wild type border cells with a 1.5 fold front to back ratio, whereas phospho-cofilin has a robust and uniform distribution pattern. Rac signaling is required for cofilin's global phosphorylation but not for its asymmetry. Importantly, we found that the guidance receptor PVR (PDGF/VEGF receptor) mediates the asymmetric localization of cofilin but doesn't affect its phosphorylation. Our results support a local excitation global inhibition (LEGI) model of chemotaxis for border cells, where an extracellular chemotactic gradient locally excites a PVR-mediated internal asymmetry of total cofilin, while an unknown receptor signals to Rac to promote global phosphorylation of cofilin, achieving spatial separation of inactive and active cofilin, with active cofilin and its lamellipodium-promoting activity largely limited to the cellular region facing the chemotactic gradient during guided migration.