![]() ![]() cAMP and cGMP often exert opposing effects on cellular responses to extracellular factors. cAMP and cGMP are among the most important second messengers in many biological processes. We set to determine the roles of cyclic mononucleotides, example cyclic AMP and cyclic GMP (cAMP and cGMP) in migration of cell fragments. Our previous study ( Sun et al., 2013) showed that keratocyte fragments respond to a direct-current electric field (dcEF), by migrating toward the anode, unlike their mother cells, that migrate toward the cathode. EF-guided cell migration, termed galvanotaxis, has been reported for many cell types including corneal epithelial cells, keratinocytes, endothelial cells, lymphocytes, stem cells, and cancer cells ( Mycielska and Djamgoz, 2004 Zhao et al., 2006 Brown and Dransfield, 2008 Lin et al., 2008 Feng et al., 2012 Yang et al., 2013 Cortese et al., 2014). We used electric fields (EFs) as a directional cue to guide migration of cell fragments. We recently developed an experimental protocol to induce directional migration of fish keratocyte fragments ( Sun et al., 2013). Cell fragments from fish keratocytes exhibit robust motility like their parental cells and provide a good model for studying the mechanisms of cell motility ( Verkhovsky et al., 1999). ![]() Thus, following multiple studies ( Rafelski and Theriot, 2004), we chose them as the experimental model for cell migration. The mechanisms underlying migration of cell fragments, however, have not been well studied and remain poorly understood.įish epidermal keratocytes move rapidly with a smooth gliding motion, while maintaining a uniform shape and speed. Cell fragments thus may play important roles in physiology and pathology through active participation in homeostasis, phagocytosis, and cell-cell communication ( Mannel and Grau, 1997 Bang and Thum, 2012 Arnold and Kahwash, 2014). Cells can also shed smaller fragments like exosomes. Migration of fragments from glioma cells correlate with malignancy ( Yount et al., 2007). Cell fragments from white blood cells (also called cytokineplasts or cytoplasts) retain chemotactic, phagocytic, and microbicidal function in vitro and in vivo ( Malawista et al., 1989 Malawista et al., 1992 Malawista et al., 2006). Recent experiments provide convincing evidence demonstrating that platelets are mobile, able to migrate over a surface, and transmigrate through a basement membrane and endothelium toward a chemoattractant source ( Kraemer et al., 2010 Schmidt et al., 2011). ![]() Blood platelets play an essential role in coagulation, and are specialized type of cells which were believed to be static and immobile once they adhere to a matrix ( Valone et al., 1974). However, cell fragments devoid of the nuclear and major organelles, in which signaling is likely very different from that of the mother cells, are also able to manifest robust motility and directional migration. Signaling networks govern cell migration ( Ridley et al., 2003). Our results suggest that cAMP and cGMP are essential for galvanotaxis of cell fragments, in contrast to the signaling mechanisms in parental cells. Inhibition of cathode signaling with PI3K inhibitor LY294002 also prevented the effects of cAMP or cGMP agonists. Both perturbations confirmed that the inhibitory effect was mediated by cAMP or cGMP signaling. Blocking cAMP and cGMP downstream signaling by inhibition of PKA and PKG also recovered fragment galvanotaxis. The inhibition effects were prevented by pre-incubating with cAMP and cGMP antagonists. cAMP or cGMP agonists completely abolished directional migration of fragments, but had no effect on parental cells. Here we used fish keratocyte fragments and demonstrated striking differences in signal transduction in migration of cell fragments and parental cells in a weak electric field. Signaling mechanisms underlying migration of cell fragments are poorly understood. Fragments from white blood cells display chemotaxis, phagocytosis, and bactericidal functions. Cell fragments devoid of the nucleus and major organelles are found in physiology and pathology, for example platelets derived from megakaryocytes, and cell fragments from white blood cells and glioma cells. ![]()
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