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Background: Epithelial tissues undergo extensive collective movements during morphogenesis, repair, and renewal. Collective epithelial cell migration requires the intercellular coordination of cell-cell adhesions and the establishment of anterior-posterior polarity, while maintaining apical-basal polarity, but how this is achieved at the molecular level is not well understood., Results: Using an RNA interference-based screen to identify Rho family GTPase regulators required for the collective migration of human bronchial epithelial cells, we identified myosin-IXA (gene name: Myo9a). Depletion of myosin-IXA, a RhoGAP and actin motor protein, in collectively migrating cells led to altered organization of the actin cytoskeleton and tension-dependent disruption of cell-cell adhesions, followed by an inability to form new adhesions resulting in cell scattering. Closer examination revealed that myosin-IXA is required during the formation of junction-associated actin bundles soon after cell-cell contact. Structure-function analysis of myosin-IXA revealed that the motor domain is necessary and sufficient for binding to actin filaments, whereas expression of the RhoGAP domain partially rescued the cell scattering phenotype induced by myosin-IXA depletion. Finally, a fluorescence resonance energy transfer biosensor revealed a significant increase in Rho activity at nascent cell-cell contacts in myosin-IXA depleted cells compared to controls., Conclusion: We propose that myosin-IXA locally regulates Rho and the assembly of thin actin bundles associated with nascent cell-cell adhesions and that this is required to sustain the collective migration of epithelial cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Collective cell migration is a key process during epithelial morphogenesis, tissue regeneration and tumor dissemination. During collective epithelial migration, anterior-posterior polarity, apical-basal polarity and cell-cell junctions must be dynamically coordinated, but the underlying molecular mechanisms controlling this complex behavior are unclear. Rho GTPases regulate the actin cytoskeleton, in particular protrusive and contractile activities at cell-cell contacts. Recently a number of regulators--nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs)--have been identified and suggested to provide spatio-temporal control of Rho GTPases at cell-cell contacts. One of these is myosin IXA, a member of class IX, single-headed actin motors having a conserved RhoGAP domain. Using its actin-binding and motor activities, myosin IX interacts with actin filaments and moves toward filament plus ends. At the plasma membrane, myosin IX's RhoGAP activity negatively regulates Rho to facilitate localized reorganization of the actin cytoskeleton. Here, I discuss how myosin IXA regulates Rho and the actin cytoskeleton during the assembly of nascent cell-cell contacts and how this might contribute to collective epithelial migration. [ABSTRACT FROM AUTHOR]