Graded distributions of extracellular cues guide developing axons toward their targets. A network of second messengers — Ca2+ and cyclic nucleotides — shapes cue-derived information into either attractive or repulsive signals that steer growth cones bidirectionally. Emerging evidence suggests that such guidance signals create a localized imbalance between exocytosis and endocytosis, which in turn redirects membrane, adhesion and cytoskeletal components asymmetrically across the growth cone to bias the direction of axon extension. These recent advances allow us to propose a unifying model of how the growth cone translates shallow gradients of environmental information into polarized activity of the steering machinery for axon guidance.

Measurements of its spatial profile reveal the crucial role of asymmetric IP₃ signals in growth cone navigation.

During development, asymmetric Ca2+ signals across the growth cone mediate bidirectional axon guidance depending on intracellular levels of cyclic AMP: Ca2+ signals trigger attractive or repulsive turning when cyclic AMP levels are high or low, respectively. Here, we report that the cell adhesion molecule L1 elevates cyclic AMP levels in neurons via ankyrinB, a protein that links the L1 cytoplasmic tail with the spectrin network. We also show that the loss of ankyrinB expression converts Ca2+-triggered attraction to repulsion when the growth cone migrates via an L1-dependent mechanism. These results indicate that ankyrinB regulates axon guidance via cyclic AMP.

Neuronal network formation relies on the motile behavior of growth cones at the tip of navigating axons. Accumulating evidence indicates that growth cone motility requires spatially controlled endocytosis and exocytosis that can redistribute bulk membrane and functional cargos such as cell adhesion molecules. For axon elongation, the growth cone recycles cell adhesion molecules from its rear to its leading front through endosomes, thereby polarizing growth cone adhesiveness along the axis of migration direction. In response to extracellular guidance cues, the growth cone turns by retrieving membrane components from the retractive side or by supplying them to the side facing the new direction. We propose that polarized membrane trafficking creates adhesion gradients along and across the front-to-rear axis of growth cones that are essential for axon elongation and turning, respectively. This review will examine how growth cone adhesiveness can be patterned by spatially coordinated endocytosis and exocytosis of cell adhesion molecules. This article is part of a Special Issue entitled 'Neuronal Function'.

Asymmetric Ca2+ elevations across the axonal growth cone mediate its turning responses to attractive and repulsive guidance cues. Here we show that clathrin-mediated endocytosis acts downstream of Ca2+ signals as driving machinery for growth cone turning. In dorsal root ganglion neurons, the formation of clathrin-coated pits is facilitated asymmetrically across the growth cone by a directionally applied chemorepellent, semaphorin 3A, or by Ca2+ signals that mediate repulsive guidance. In contrast, coated pit formation remains symmetric in the presence of attractive Ca2+ signals. Inhibition of clathrin-mediated endocytosis abolishes growth cone repulsion, but not attraction, induced by Ca2+ or extracellular physiological cues. Furthermore, asymmetric perturbation of the balance of endocytosis and exocytosis in the growth cone is sufficient to initiate its turning toward the side with less endocytosis or more exocytosis. With our previous finding that growth cone attraction involves asymmetric exocytosis, we propose that the balance between membrane addition and removal dictates bidirectional axon guidance.Highlights► Guidance cues repel growth cones via asymmetric clathrin-mediated endocytosis ► Repulsive, but not attractive, Ca2+ signals cause asymmetric endocytosis ► Altering the balance of endocytosis/exocytosis is sufficient to initiate axon turning ► The growth cone turns toward the side with less endocytosis or more exocytosis