Abstract
Migrating cells and growth cones extend lamellipodial and filopodial protrusions that are required for outgrowth and guidance. The mechanisms of cytoskeletal regulation that underlie cell and growth cone migration are of much interest to developmental biologists. Previous studies have shown that the Arp2/3 complex and UNC-115/abLIM act redundantly to mediate growth cone lamellipodia and filopodia formation and axon pathfinding. While much is known about the regulation of Arp2/3, less is known about regulators of UNC-115/abLIM. Here we show that the Caenorhabditis elegans counterpart of the Receptor for Activated C Kinase (RACK-1) interacts physically with the actin-binding protein UNC-115/abLIM and that RACK-1 is required for axon pathfinding. Genetic interactions indicate that RACK-1 acts cell-autonomously in the UNC-115/abLIM pathway in axon pathfinding and lamellipodia and filopodia formation, downstream of the CED-10/Rac GTPase and in parallel to MIG-2/RhoG. Furthermore, we show that RACK-1 is involved in migration of the gonadal distal tip cells and that the signaling pathways involved in this process might be distinct from those involved in axon pathfinding. In sum, these studies pinpoint RACK-1 as a component of a novel signaling pathway involving Rac GTPases and UNC-115/abLIM and suggest that RACK-1 might be involved in the regulation of the actin cytoskeleton and lamellipodia and filopodia formation in migrating cells and growth cones.
Highlights
The actin cytoskeleton is necessary for the formation of cellular protrusions, lamellipodia and filopodia, that underlie morphogenetic events such as cell migration and axon pathfinding [1,2,3,4]
The genes that are involved in lamellipodia and filopodia formation in the growth cone are still being discovered, and studies to understand how these genes act together in cell signaling events that control growth cone movement are in their infancy
We report discovery of a new gene necessary for growth cone movement in Caenorhabditis elegans called rack-1. This gene is conserved in vertebrates and is involved in cellular signaling. We show that it interacts in a novel manner with other cell signaling genes and a gene involved in lamellipodia and filopodia formation, called unc-115/abLIM
Summary
The actin cytoskeleton is necessary for the formation of cellular protrusions, lamellipodia and filopodia, that underlie morphogenetic events such as cell migration and axon pathfinding [1,2,3,4]. In migrating growth cones in C. elegans, the Arp2/3 complex is required for both lamellipodial and filopodial formation [16], likely due to the contribution of Arp2/3-nucleated actin filaments to filopodial bundles [7]. The actin-binding protein UNC-115/abLIM [17] controls lamellipodial and filopodial formation in C. elegans growth cones [16], and acts in parallel to the Arp2/3 complex in axon pathfinding [16,17,18], indicating that UNC-115/abLIM may be contributing to both lamellipodial and filopodial formation in growth cones. In C. elegans axon pathfinding, WVE-1/WAVE acts downstream of CED-10/Rac and WSP-1/WASP acts downstream of the MIG2/RhoG GTPase to regulate Arp2/3 [18]
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