Intracellular signaling and membrane trafficking control bidirectional growth cone guidance

The formation of precise neuronal networks is critically dependent on the motility of axonal growth cones. Extracellular gradients of guidance cues evoke localized Ca2+ elevations to attract or repel the growth cone. Recent studies strongly suggest that the polarity of growth cone guidance, with respect to the localization of Ca2+ signals, is determined by Ca2+ release from the endoplasmic reticulum (ER) in the following manner: Ca2+ signals containing ER Ca2+ release cause growth cone attraction, while Ca2+ signals without ER Ca2+ release cause growth cone repulsion. Recent studies have also shown that exocytic and endocytic membrane trafficking can drive growth cone attraction and repulsion, respectively, downstream of Ca2+ signals. Most likely, these two mechanisms underlie cue-induced axon guidance, in which a localized imbalance between exocytosis and endocytosis dictates bidirectional growth cone steering. In this Update Article, I summarize recent advances in growth cone research and propose that polarized membrane trafficking plays an instructive role to spatially localize steering machineries, such as cytoskeletal components and adhesion molecules.

► Ca2+ release from the endoplasmic reticulum mediates attractive axon guidance.
► Ca2+ signals without Ca2+ release favor repulsive axon guidance.
► Exocytic membrane trafficking drives Ca2+-induced growth cone attraction.
► Endocytic membrane trafficking drives Ca2+-induced growth cone repulsion.
► The imbalance between exocytosis and endocytosis dictates bidirectional axon guidance.