Nerve growth cone guidance mediated by G protein–coupled receptors

Abstract

Growing axons navigate by responding to chemical guidance cues. Here we report that growth cones of rat cerebellar axons in culture turned away from a gradient of SDF-1, a chemokine that attracts migrating leukocytes and cerebellar granule cells via a G protein-coupled receptor (GPCR). Similarly, Xenopus spinal growth cones turned away from a gradient of baclofen, an agonist of the GABA(B) receptor. This response was mediated by G(i) and subsequent activation of phospholipase C (PLC), which triggered two pathways: protein kinase C (PKC) led to repulsion, and inositol 1,4,5-triphosphate (IP(3)) receptor activation led to attractive turning. Under normal culture conditions, PKC-dependent repulsion dominated, but the repulsion could be converted to attraction by inhibiting PKC or by elevating cytosolic cGMP. Thus, GPCRs can mediate both repulsive and attractive axon guidance in vitro, and chemokines may serve as guidance cues for axon pathfinding.

Asymmetric redistribution of GABA receptors during GABA gradient sensing by nerve growth cones analyzed by single quantum dot imaging

“…6]. These observations are in agreement with previous reports identifying GABA as a chemoattractant (16).…”

“…We developed a single-molecule assay in which the spatiotemporal dynamics of the distribution of individual GABA A Rs is monitored in response to a GABA gradient. The role of GABA as chemoattractant, like other neurotransmitters such as acetylcholine (Ach) and glutamate (8), has been previously documented (16). Our assay takes advantage of the brightness and photostability of quantum dots (QDs), which are used to fluorescently tag GABA A Rs and to track them at the single-nanoparticle level over long durations (tens of minutes), with good signal-to-noise ratio (Ϸ30) and with high localization accuracy (Ϸ10 nm) (17,18).…”

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

“…Because guidance by a number of guidance cues has been shown to depend on both Rho family activity and local protein synthesis and degradation ( general events required for directional steering of growth cones in response to various guidance cues. Recent evidence suggests that GPCRs may have a role in axon guidance (Xiang et al, 2002). Our studies provide direct evidence that PACAP activation of its GPCR elicits attractive turning responses from growth cones.…”

Chemokine receptor expression by neural progenitor cells in neurogenic regions of mouse brain

“…These cells appear to include the population of young PSA-NCAM-positive granule neurons. Several previous studies have commented on the association of these PSA-NCAM-positive cells with neural progenitor cells and other young granule neurons in the SGZ/DG (Seki, 2002a(Seki, ,b, 2003.Given the chemoattractant role that SDF-1 plays for CXCR4-expressing progenitors during DG development (Bagri et al, 2002;Lu et al, 2002), and its additional role as an axonal guidance cue (Xiang et al, 2002;Arakawa et al, 2003;Chalasani et al, 2003;Pujol et al, 2005), it seems reasonable to suggest that release of SDF-1 from young granule neurons may be involved in guiding the migration and development of CXCR4-expressing progenitors and immature granule cells as they move from the SGZ into the granule cell layer proper.With respect to the SVZ and OB, we can similarly conclude that CXCR4 receptors are expressed by populations of neural progenitors in these areas. The localization of neural progenitors in the SVZ is also well established and, as in the DG, the pathway by which these cells subsequently develop has been defined in detail (Alvarez-Buylla and Lim, 2004;Merkle et al, 2004).…”

“…Indeed, it is clear that the chemokine SDF-1 and its receptor CXCR4 play an important role in the development of the nervous system and other tissues. In the nervous system, SDF-1/CXCR4 signaling directs the migration of neural stem cells to a number of different parts of the brain (Zou et al, 1998;Bagri et al, 2002;Lu et al, 2002;Stumm et al, 2003) and the DRG (Belmadani et al, 2005) and also plays a role as an axonal guidance cue (Xiang et al, 2002;Arakawa et al, 2003;Chalasani et al, 2003;Lieberam et al, 2005;Pujol et al, 2005). It has also been demonstrated that neurospheres prepared from postnatal brains express CXCR4 as well as other chemokine receptors (Lazarini et al, 2000;Stumm et al, 2003;Ji et al, 2004;Peng et al, 2004;Tran et al, 2004) and that chemokines act as chemoattractants for these cells (Pluchino et al, 2005;Tran et al, 2004Tran et al, , 2005Widera et al, 2004), suggesting that chemokine-mediated effects may also be important in the regulation of adult progenitor cell migration.…”