Molecular signatures of cell migration in C . elegans Q

Cell migration is an essential feature of metazoan development and also plays important roles in the physiology of adult organisms (Lehmann, 2001; Locascio and Nieto, 2001). Impaired cell migration results in various developmental disorders such as congenital brain defects, and excessive migration also contributes to pathologies such as tumor metastasis (http://www.cellmigration .org; Yamaguchi et al., 2005; Kurosaka and Kashina, 2008). Considerable progress has been made in identifying the protein machinery that drives migration and the extracellular signals that guide migration (Webb et al., 2002; Pollard and Borisy, 2003; Ridley et al., 2003; Jaffe and Hall, 2005; Simpson et al., 2008). However, molecular mechanisms that control the speed and distance of cell migration in vivo are largely unknown. Why do some cells migrate away from their birth place while others remain? For those migrating cells, why do some cells migrate faster and further than others? Knowledge obtained from in vitro cultured cells offers a good starting point for understanding cell migration in live animals. However, cellular behavior in a 3D tissue shows several distinct properties from a 2D culturing condition (Yamada and Cukierman, 2007). Thus, investigations of cell migration in live metazoans are necessary to understand how molecular pathways discovered through in vitro model systems operate in living organisms. To best study cell migration in live animals, one needs single cell resolution so that one can follow a cell’s trajectory and changes in speed. Ideally, one would like to compare different cells that have different migration patterns so that one might be able to identify molecular differences that might underlie these distinct migratory capacities. Caenorhabditis elegans Q neuroblasts have the potential of being such an attractive model system. Pioneering work of C. elegans post-embryonic development reported that descendants of Q neuroblasts migrate different distances during the L1 larva stage (Sulston and Horvitz, 1977). Previous observations of Q neuroblast development mainly relied on Nomarski optics (Sulston and Horvitz, 1977). In this study, we developed GFP-based live cell time-lapse imaging methodologies to document Q neuroblast development with spinning-disk confocal microscopy. We found that descendants in the Q neuroblast lineage have distinct migratory speeds and distances, making it an appealing model to discover the molecular differences among descendants of Q neuroblasts. We provide evidence that MIG-2, a Rho family GTPase mutant (Zipkin et al., 1997), and INA-1, an integrin  subunit mutant (Baum and Garriga, 1997), play important but distinct roles in defining the distinct migratory behavior of Q descendants. Metazoan cell movement has been studied extensively in vitro, but cell migration in living animals is much less well understood. In this report, we have studied the Caenorhabditis elegans Q neuroblast lineage during larval development, developing live animal imaging methods for following neuroblast migration with single cell resolution. We find that each of the Q descendants migrates at different speeds and for distinct distances. By quantitative green fluorescent protein imaging, we find that Q descendants that migrate faster and longer than their sisters up-regulate protein levels of MIG-2, a Rho family guanosine triphosphatase, and/or down-regulate INA-1, an integrin  subunit, during migration. We also show that Q neuroblasts bearing mutations in either MIG-2 or INA-1 migrate at reduced speeds. The migration defect of the mig-2 mutants, but not ina-1, appears to result from a lack of persistent polarization in the direction of cell migration. Thus, MIG-2 and INA-1 function distinctly to control Q neuroblast migration in living C. elegans. Molecular signatures of cell migration in C. elegans Q neuroblasts