The PDZ-GEF dizzy regulates cell shape of migrating macrophages via Rap1 and integrins in the Drosophila embryo.
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.
Huelsmann
Sven
S
Interfakultäres Institut für Zellbiologie, Abteilung Genetik der Tiere, Fakultät für Biologie, Universität Tübingen, Auf der Morgenstelle 28, D-72076 Tübingen, Germany.
Hepper
Christina
C
Marchese
Daniele
D
Knöll
Christian
C
Reuter
Rolf
R
D000818:Animals; D030801:Animals, Genetically Modified; D002448:Cell Adhesion; D002465:Cell Movement; D048430:Cell Shape; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D017931:DNA Primers; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000502:physiology*; D016678:Genome; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D016023:Integrins / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D017931:DNA Primers; D029721:Drosophila Proteins; D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; C514059:PDZ-GEF protein, Drosophila; D004247:DNA; D020827:rap1 GTP-Binding Proteins