Directed cell migration (chemotaxis) is a fundamental biological process
necessary for embryonic development, wound healing, and proper function of
the immune system. Chemotaxis also plays a significant role in many
developmental disorders and post-embryonic diseases in humans, such as
cancer. Chemotaxis is driven by extracellular cues that act, in large part, to
induce changes in the actin cytoskeleton, such as actin polymerization, that
facilitate directed cell migration.
Myosins are actin-associated motors that have a variety of functions in
different cellular contexts. Myosins can effect cortical tension, pseudopod and
filopodia formation, phagocytosis, the function of sensory structures, and the
basic mechanics of cell motility. Members of the MyTH/FERM family of
unconventional myosins all have roles in actin-based processes and one
member, vertebrate myosin X, has recently been shown to play a role in actin
dynamics in response to extracellular migration cues.
The social amoeba Dictyostelium discoideum is a powerful model system
for dissecting chemoattractant signaling pathways and identifying the
cytoskeletal components necessary for directed cell migration. MyoG is a novel
unconventional myosin characterized by two MyTH/FERM domains in its tail
region. The potential role of this myosin in Dictyostelium cell migration was
investigated by analyzing the phenotype of three independent myoG null
mutants. The initial stages of Dictyostelium development, induced by starvation,
depend on chemotaxis to cAMP, resulting in the formation of a multi-cellular
aggregate. Upon starvation myoG — cells fail to aggregate, arresting as a
smooth monolayer of cells. The myoG — cells neither polarize in a cAMP
gradient nor do they chemotax toward the cAMP source. Analysis of the ability
of myoG — cells to polymerize actin in response to cAMP revealed that the
response is dampened in the mutants. myoG — cells are also defective in
signaling to PI3K in response to cAMP. These data show that while the mutant
cells retain some ability to respond to the gradient, the major pathways
regulating polarity and chemotaxis are not functional. The mutant phenotype
suggests that MyoG acts in transducing the chemotactic signal from the cAMP
receptor to PI3K and the actin cytoskeleton, facilitating the morphological
changes that lead to polarization and directional migration.
The role of MyoG in chemotactic signaling represents a novel function for
an unconventional myosin. The work presented here clearly demonstrates that
MyoG is necessary for signaling from the cAMP receptor to both PI3K and the
actin cytoskeleton. Sequence analysis shows that there is no direct homologue
of MyoG in other organisms, but the high degree of conservation of the
chemotactic signaling pathways indicates that there are likely to be functional
homologues in higher eukaryotic cells, such as neutrophils, that rely on
chemotaxis for cellular function.
University of Minnesota Ph.D. dissertation. August 2009. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Dr. Margaret A. Titus. 1 computer file (PDF); x, 132 pages, appendix (pages 92-123)
Breshears, Laura Marie.
An unconventional myosin is necessary for chemotaxis in Dictyostellium discoideum..
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