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Second messengers and membrane trafficking direct and organize growth cone steering
Takuro Tojima*, Jacob H.Hines, John R.Henley and Hiroyuki Kamiguchi*
Abstract | 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.
The formation of functional neuronal networks depends crucially on the spatial accuracy of axon growth and navigation. Each growing axon in the developing nervous syste m is tipped by a growth cone, a specialized amoeboid structure that is able to interpret secreted and membrane-bound molecular guidance cues that direct its migration along the correct path. A series of these events deliver the axon to an approximate target region, which is typically followed by axonal arborization and contact with appropriate postsynaptic partners at particular sub cellular locations1. Such specificity of synaptic connections within the target region relies on multiple distinct mechanisms including further cue-mediated axon guidance2,3. In this way, guidance cues in the microenvironment play crucial parts in neuronal network formation.
It is widely accepted that graded distribution of guidance cues controls the direction of axon growth (FIG.1a).
Such gradients can be generated by diffusion of a secreted cue away from its source of synthesis4 or by differentia l expression of non-diffusible cues5. When a growth cone migrates in a guidance cue gradient, the side of the growth cone facing higher concentrations of the cue will experience higher receptor occupancy. This asymmetric receptor occupancy polarizes the growth cone for turning either toward increasing concentrations of the cue (attraction) or away from the cue (repulsion), through intracellular generation of second messengers such as Ca2+ and cyclic nucleotides611. An extracellular shallow gradient can be transformed into steeply graded12 or, in extreme cases, compartmentalized signals11,13 inside
the growth cone. The asymmetrically produced second messengers...