Signal Transduction in Neuronal Migration

Abstract

The Slit protein guides neuronal and leukocyte migration through the transmembrane receptor Roundabout (Robo). We report here that the intracellular domain of Robo interacts with a novel family of Rho GTPase activating proteins (GAPs). Two of the Slit-Robo GAPs (srGAPs) are expressed in regions responsive to Slit. Slit increased srGAP1-Robo1 interaction and inactivated Cdc42. A dominant negative srGAP1 blocked Slit inactivation of Cdc42 and Slit repulsion of migratory cells from the anterior subventricular zone (SVZa) of the forebrain. A constitutively active Cdc42 blocked the repulsive effect of Slit. These results have demonstrated important roles for GAPs and Cdc42 in neuronal migration. We propose a signal transduction pathway from the extracellular guidance cue to intracellular actin polymerization.

Inhibition of medulloblastoma cell invasion by Slit

“…We have demonstrated decreased Cdc42 activation for medulloblastoma cells in response to Slit2. This agrees with previous results obtained by Wong et al (2001). Therefore, there may be a conserved mechanism regulating both the repellent and inhibitory response to Slit2.…”

“…This treatment had no effect on expression levels of both Slit2 and Robo1 in the cell lines tested. Wong et al (2001) have demonstrated a role for the srGAPs (Slit-Robo GAPs) in Slit-Robo signaling. Interaction of srGAP's with the Rho-GTPase, Cdc42 is essential for the repulsive activity of this guidance cue (Wong et al, 2001).…”

“…Wong et al (2001) have demonstrated a role for the srGAPs (Slit-Robo GAPs) in Slit-Robo signaling. Interaction of srGAP's with the Rho-GTPase, Cdc42 is essential for the repulsive activity of this guidance cue (Wong et al, 2001). Other studies support a role for Phosphatidyl inositol 3 kinase, Dock and Pak, and the Abelson (Abl) kinase and Enabled (Ena) proteins further implicating actin and microtubule reorganization in Slit-Robo signaling (Bashaw et al, 2000;Fan et al, 2003;Wang et al, 2003).…”

“…Cdc42 and Rac1 play roles in Slit-mediated repulsion (Wong et al, 2001;Fan et al, 2003;Lundstrom et al, 2004). To assess Rho-GTPase activation by Slit2, medulloblastoma and glioma cells were cultured in medium conditioned by HEK or Slit2 cells and pulldown assays of activated Cdc42, Rac1 and RhoA were conducted.…”

Neutrophil polarization: Spatiotemporal dynamics of RhoA activity support a self-organizing mechanism

“…Phosphoinositide 3-kinases (PI3Ks), Rho GTPases such as RhoA, Rac, and Cdc42, and the actin and microtubule cytoskeletons play key roles in signaling polarity in cells ranging from Dictyostelium discoideum (3)(4)(5)(6) to neurons (7)(8)(9)(10)(11)(12) and human neutrophils (5,(13)(14)(15)(16)(17). Neutrophils and dHL-60 cells show an unusually strong inherent propensity to polarize.…”