Lipid Rafts Mediate Chemotropic Guidance of Nerve Growth Cones

Abstract

Axon guidance requires signal transduction of extracellular cues through the plasma membrane for directional motility. Here we present evidence that cholesterol- and sphingolipid-enriched membrane microdomains (lipid rafts) mediate specific guidance responses of nerve growth cones. Disruption of lipid rafts by various approaches targeting cholesterol or gangliosides selectively abolished growth cone attraction and repulsion in BDNF and netrin-1 gradients, respectively, without affecting glutamate-induced attraction. Interestingly, local raft disruption on one side of the growth cone in bath BDNF or netrin-1 produced opposite turning responses to that induced by the gradients. Raft manipulation also blocked Semaphorin 3A-induced growth cone repulsion, inhibition, and collapse. Finally, guidance responses appeared to involve raft-dependent activation of p42/p44 MAPK and ligand-induced receptor recruitment to lipid rafts. Together with the observation of asymmetric receptor-raft associations at the growth cone in guidance gradients, our findings indicate that localized signaling through membrane rafts plays a role in mediating guidance actions of extracellular cues on developing axons.

MDGA1, an IgSF molecule containing a MAM domain, heterophilically associates with axon- and muscle-associated binding partners through distinct structural domains

“…Here we report some fundamental characteristics of this molecule that could be informative for analyzing its functions in tumorigenesis and differentiation in the CNS, including in the basilar pons. A recent report showing that MDGA1 is localized to lipid rafts (DiazLopez et al, 2005) may support the idea that MDGA1 modulates the behavior of growth cones, since lipid rafts reportedly mediate chemotropic guidance of growth cones (Guirland et al, 2004). Studies of MDGA1 in different biological phenomena may lead to the unmasking of a previously uncharacterized general mechanism for modulating axon outgrowth and cell motility.…”

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…In the brain, lipid rafts concentrate and organize cell adhesion molecules and cytoskeletal machinery for axonal growth and guidance (Guirland et al 2004;Kamiguchi 2006). The localization of the calcium/calmodulin-dependent protein Takemoto-Kimura et al 2007).…”

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

“…However, the asymmetric localization of lipid rafts and raft-associated tyrosine kinase B receptors after exposure to a brain-derived neurotrophic factor gradient has been reported (13). Given the alleged role of rafts as signaling platforms, the membrane reorganization could serve to locally enhance the sensing efficiency at the GC leading edge by regulating the number of active receptors; however, the timing and the mechanism of the reorganization are unknown.…”