Axon Guidance GPCRs Mediate Axon Repulsion

Chemokines, first identified for chemoattractant activity for immune cells, are now becoming recognized as migratory signals in the central nervous system. So far, they have been implicated in both neuron and glial cell migration (see the Related Resources). Xiang et al. provide evidence that a gradient of the chemokine stromal-derived factor-1 (SDF-1) can repel axon growth of cultured cerebellar granule cells, promoting repulsive axon turning that was inhibited by an antibody against the chemokine receptor CXCR4. Chemokines activate G protein-coupled receptors (GPCRs). In Xenopus spinal neurons, repulsive turning was stimulated by the addition of a gradient of the metabotropic (GPCR) -aminobutyric acid (GABA_B) receptor activator, baclofen. GABA itself promoted chemoattraction of these neurons through stimulation of the ionotropic GABA_A receptor. Chemorepulsion was inhibited by inhibitors of G_i or phospholipase C (PLC) or depletion of internal calcium stores. Repulsion could be converted to attraction by the addition of the guanosine 3',5'-monophosphate (cGMP) analog 8-Br-cGMP or by the addition of protein kinase C (PKC) inhibitors. The authors suggest that a gradient of GPCR activation can stimulate growth cone turning. Whether the response is an attractive or repulsive one depends on the cGMP concentration.

Y. Xiang, Y. Li, Z. Zhang, K. Cui, S. Wang, X.-b. Yuan, C.-p. Wu, M.-m. Poo, S. Duan, Nerve growth cone guidance mediated by G protein-coupled receptors, Nature Neurosci. 5, 843-8448 (2002). [Online Journal]