The PDZ-GEF dizzy regulates cell shape of migrating macrophages via Rap1 and integrins in the Drosophila embryo.
2006
In Drosophila embryos, macrophages originate from the cephalic
mesoderm and perform a complex migration throughout the entire embryo. The
molecular mechanisms regulating this cell migration remain largely unknown. We
identified the Drosophila PDZ G-nucleotide exchange factor (PDZ-GEF)
Dizzy as a component essential for normal macrophage migration. In mutants
lacking Dizzy, macrophages have smaller cellular protrusions, and their
migration is slowed down significantly. This phenotype appears to be
cell-autonomous, as it is also observed in embryos with a dsRNA-induced
reduction of dizzy function in macrophages. In a complementary
fashion, macrophages overexpressing Dizzy are vastly extended and form very
long protrusions. These cell shape changes depend on the function of the small
GTPase Rap1: in rap1 mutants, Dizzy is unable to induce the large
protrusions. Furthermore, forced expression of a dominant-active form of Rap1,
but not of the wild-type form, induces similar cell shape changes as Dizzy
does overexpression. These findings suggest that Dizzy acts through Rap1. We
propose that integrin-dependent adhesion is a Rap1-mediated target of Dizzy
activity: in integrin mutants, neither Dizzy nor Rap1 can induce cell shape
changes in macrophages. These data provide the first link between a PDZ-GEF,
the corresponding small GTPase and integrin-dependent cell adhesion during
cell migration in embryonic development.
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