Cell migration is critical for animal development and organogenesis, and inappropriate cell migration contributes to progression of diseases such as metastatic cancer. We are using migration of two specialized C. elegans cells, the distal tip cells (DTC), as an in vivo model system to elucidate the mechanisms by which cells convert extracellular cues to cell migratory behaviors. The genes controlling DTC migration, including metalloproteases, integrins, and Rac GTPases, are strikingly similar to the genes required during metastasis. The goal of the proposed study is to elucidate the mechanism of action of W03H9.4, a novel regulator of in vivo cell migration required for correct timing of DTC turns and correct DTC pathfinding. Our working hypothesis, based on preliminary evidence, is that W03H9.4 controls the cell polarity and directional cell migration of the DTC by regulating the expression pattern or sub-cellular localization of proteins, including netrin guidance cues and/or netrin receptor proteins, which results in altered Rac GTPase signaling and defective cell guidance. First, the cell types and developmental stages that require W03H9.4 for function will be determined through analysis of transgenic animals expressing GFP fusion proteins and immunofluorescence with 1W03H9.4 antibodies. Secondly, the mechanism of W03H9.4 action will be investigated through transgenic rescue of W03H9.4(tm3042) mutant animals, cell-type specific overexpression of W03H9.4, and cell-type specific depletion of W03H9.4 by RNAi. Finally, genetic interactions between W03H9.4, the netrin signaling system, and Rac family GTPases will be investigated, and the effect of disrupted W03H9.4 levels on localization or expression of these signaling proteins will be determined. The exciting connection between W03H9.4 and Rac GTPases gives this study tremendous potential to improve our understanding of the fundamental regulation of cell migration during animal development and in pathologic conditions such as metastatic cancer.

Public Health Relevance

We are using migratory cells in the nematode C. elegans as a model system to study genes involved in cell migration processes, particularly those genes that are relevant to metastatic cancer. This study will determine how a novel gene, W03H9.4, helps cells correctly interpret the extracellular cues that let cells know when to migrate and when to stop migrating. The connection between W03H9.4 and known signaling cascades gives this study tremendous potential to improve our understanding of the fundamental regulation of cell migration during animal development and in pathologic conditions such as metastatic cancer.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Intercellular Interactions (ICI)
Program Officer
Nie, Zhongzhen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northeastern University
Schools of Arts and Sciences
United States
Zip Code
Doherty, Michael F; Adelmant, Guillaume; Cecchetelli, Alyssa D et al. (2014) Proteomic analysis reveals CACN-1 is a component of the spliceosome in Caenorhabditis elegans. G3 (Bethesda) 4:1555-64
LaBonty, Melissa; Szmygiel, Cleo; Byrnes, Lauren E et al. (2014) CACN-1/Cactin plays a role in Wnt signaling in C. elegans. PLoS One 9:e101945
Kovacevic, Ismar; Orozco, Jose M; Cram, Erin J (2013) Filamin and phospholipase C-ýý are required for calcium signaling in the Caenorhabditis elegans spermatheca. PLoS Genet 9:e1003510
Kovacevic, Ismar; Ho, Richard; Cram, Erin J (2012) CCDC-55 is required for larval development and distal tip cell migration in Caenorhabditis elegans. Mech Dev 128:548-59
DeMaso, Christina R; Kovacevic, Ismar; Uzun, Alper et al. (2011) Structural and functional evaluation of C. elegans filamins FLN-1 and FLN-2. PLoS One 6:e22428
Tannoury, Hiba; Rodriguez, Varenka; Kovacevic, Ismar et al. (2010) CACN-1/Cactin interacts genetically with MIG-2 GTPase signaling to control distal tip cell migration in C. elegans. Dev Biol 341:176-85
Kovacevic, Ismar; Cram, Erin J (2010) FLN-1/filamin is required for maintenance of actin and exit of fertilized oocytes from the spermatheca in C. elegans. Dev Biol 347:247-57