Rac1 and Cdc42 but not RhoA or Rho kinase activities are required for neurite outgrowth induced by the Netrin-1 receptor DCC (deleted in colorectal cancer) in N1E-115 neuroblastoma cells.
Netrins are chemotropic guidance cues that attract or repel growing axons during development. DCC (deleted in colorectal cancer), a transmembrane protein that is a receptor for netrin-1, is implicated in mediating both responses. However, the mechanism by which this is achieved remains unclear. Here we report that Rho GTPases are required for embryonic spinal commissural axon outgrowth induced by netrin-1. Using N1E-115 neuroblastoma cells, we found that both Rac1 and Cdc42 activities are required for DCC-induced neurite outgrowth. In contrast, down-regulation of RhoA and its effector Rho kinase stimulates the ability of DCC to induce neurite outgrowth. In Swiss 3T3 fibroblasts, DCC was found to trigger actin reorganization through activation of Rac1 but not Cdc42 or RhoA. We detected that stimulation of DCC receptors with netrin-1 resulted in a 4-fold increase in Rac1 activation. These results implicate the small GTPases Rac1, Cdc42, and RhoA as essential components that participate in signaling the response of axons to netrin-1 during neural development.
Li
Xiaodong
X
Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 2B2, Canada.
Saint-Cyr-Proulx
Etienne
E
Aktories
Klaus
K
Lamarche-Vane
Nathalie
N
D016475:3T3 Cells; D000818:Animals; D001369:Axons; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000502:physiology*; D000075389:DCC Receptor; D017931:DNA Primers; D051379:Mice; D008856:Microscopy, Fluorescence; D000075386:Netrin Receptors; D016501:Neurites; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; D017931:DNA Primers; C501910:Dcc protein, mouse; D000075386:Netrin Receptors; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein