Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration (Plenary Paper) Journal Article

Author(s): Lämmermann, Tim; Renkawitz, Jörg; Wu, Xunwei; Hirsch, Karin; Brakebusch, Cord; Sixt, Michael
Article Title: Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration (Plenary Paper)
Abstract: Mature dendritic cells (DCs) moving from the skin to the lymph node are a prototypic example of rapidly migrating amoeboid leukocytes. Interstitial DC migration is directionally guided by chemokines, but independent of specific adhesive interactions with the tissue as well as pericellular proteolysis. Instead, the protrusive flow of the actin cytoskeleton directly drives a basal mode of locomotion that is occasionally supported by actomyosin contractions at the trailing edge to propel the cell's rigid nucleus. We here delete the small GTPase Cdc42 in DCs and find that actin flow and actomyosin contraction are still initiated in response to chemotactic cues. Accordingly, the cells are able to polarize and form protrusions. However, in the absence of Cdc42 the protrusions are temporally and spatially dysregulated, which leads to impaired leading edge coordination. Although this defect still allows the cells to move on 2-dimensional surfaces, their in vivo motility is completely abrogated. We show that this difference is entirely caused by the geometric complexity of the environment, as multiple competing protrusions lead to instantaneous entanglement within 3-dimensional extracellular matrix scaffolds. This demonstrates that the decisive factor for migrating DCs is not specific interaction with the extracellular environment, but adequate coordination of cytoskeletal flow.
Keywords: Animals; Cells, Cultured; Mice; Mice, Knockout; Cell Differentiation; Dendritic Cells/*cytology/*metabolism; *Cell Movement/drug effects; Chemokine CCL19/pharmacology; cdc42 GTP-Binding Protein/genetics/*metabolism
Journal Title: Blood
Volume: 113
Issue 23
ISSN: 1528-0020
Publisher: American Society of Hematology  
Publication Place: United States
Date Published: 2009-06-04
Start Page: 5703
End Page: 5710
DOI: 10.1182/blood-2008-11-191882
Notes: We thank Sylvia Cremer for help with statistics and critical reading of the paper and Reinhard Fässler for continuous support. This work was supported by the German Research Foundation (Bonn, Germany), the Peter Hans Hofschneider Foundation for Experimental Biomedicine (Zürich, Switzerland), and the Max Planck Society (Munich, Germany).
Open access: no