Abstract
Many cells in a developing embryo, including neurons and their axons and growth cones, must integrate multiple guidance cues to undergo directed growth and migration. The UNC-6/netrin, SLT-1/slit, and VAB-2/Ephrin guidance cues, and their receptors, UNC-40/DCC, SAX-3/Robo, and VAB-1/Eph, are known to be major regulators of cellular growth and migration. One important area of research is identifying the molecules that interpret this guidance information downstream of the guidance receptors to reorganize the actin cytoskeleton. However, how guidance cues regulate the actin cytoskeleton is not well understood. We report here that UNC-40/DCC, SAX-3/Robo, and VAB-1/Eph differentially regulate the abundance and subcellular localization of the WAVE/SCAR actin nucleation complex and its activator, Rac1/CED-10, in the Caenorhabditis elegans embryonic epidermis. Loss of any of these three pathways results in embryos that fail embryonic morphogenesis. Similar defects in epidermal enclosure have been observed when CED-10/Rac1 or the WAVE/SCAR actin nucleation complex are missing during embryonic development in C. elegans. Genetic and molecular experiments demonstrate that in fact, these three axonal guidance proteins differentially regulate the levels and membrane enrichment of the WAVE/SCAR complex and its activator, Rac1/CED-10, in the epidermis. Live imaging of filamentous actin (F-actin) in embryos developing in the absence of individual guidance receptors shows that high levels of F-actin are not essential for polarized cell migrations, but that properly polarized distribution of F-actin is essential. These results suggest that proper membrane recruitment and activation of CED-10/Rac1 and of WAVE/SCAR by signals at the plasma membrane result in polarized F-actin that permits directed movements and suggest how multiple guidance cues can result in distinct changes in actin nucleation during morphogenesis.
Highlights
Cell migration in response to signals from outside the cell drives developmental processes from embryonic morphogenesis and the establishment of the nervous system, to aberrant migrations during diseases like metastatic cancer
Neuronal regeneration studies have benefited from genetic studies that identified the molecules that work during embryonic development to give neurons their plasticity and dynamism
We find that the actin-nucleation regulating WAVE/SCAR complex molecules, which are conserved from the C. elegans soil nematodes to human beings, are localized and regulated by axonal guidance signals during embryonic development
Summary
Cell migration in response to signals from outside the cell drives developmental processes from embryonic morphogenesis and the establishment of the nervous system, to aberrant migrations during diseases like metastatic cancer. It has been proposed that outside signals lead to cellular movements through the rearrangement of the F-actin cytoskeleton. The details of how this is accomplished are still being worked out Understanding this process will require understanding how the outside signals are able to organize the cellular cytoskeleton. In this study we addressed what specific changes in the actin cytoskeleton occurred when different migration signals were removed. We asked if changes in the levels or localization of specific F-actin regulators in response to the migration signals could explain the changes in the actin cytoskeleton and in cell migration
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