Abstract
Determining how axon guidance receptors transmit signals to allow precise pathfinding decisions is fundamental to our understanding of nervous system development and may suggest new strategies to promote axon regeneration after injury or disease. Signaling mechanisms that act downstream of four prominent families of axon guidance cues--netrins, semaphorins, ephrins, and slits--have been extensively studied in both invertebrate and vertebrate model systems. Although details of these signaling mechanisms are still fragmentary and there appears to be considerable diversity in how different guidance receptors regulate the motility of the axonal growth cone, a number of common themes have emerged. Here, we review recent insights into how specific receptors for each of these guidance cues engage downstream regulators of the growth cone cytoskeleton to control axon guidance.
Highlights
Signaling from Axon Guidance ReceptorsDetermining how axon guidance receptors transmit signals to allow precise pathfinding decisions is fundamental to our understanding of nervous system development and may suggest new strategies to promote axon regeneration after injury or disease
Endocytosis may be a necessary aspect of guidance receptor activation and signaling
Other studies in rodent commissural neurons support a different role for cAMP/protein kinase A (PKA) in contributing to Netrin responses and have shown: (1) that Netrin does not lead to elevations in cAMP levels or activation of PKA, (2) that PKA is not required for Netrin attraction, but instead regulates the Netrin response through promoting DCC recruitment to the plasma membrane, and (3) that mutations in soluble adenylyl cyclase do not result in commissural axon guidance defects in mice (Bouchard et al 2004; Moore and Kennedy 2006; Moore et al 2008b)
Summary
Determining how axon guidance receptors transmit signals to allow precise pathfinding decisions is fundamental to our understanding of nervous system development and may suggest new strategies to promote axon regeneration after injury or disease. Signaling mechanisms that act downstream of four prominent families of axon guidance cues—netrins, semaphorins, ephrins, and slits—have been extensively studied in both invertebrate and vertebrate model systems. Details of these signaling mechanisms are still fragmentary and there appears to be considerable diversity in how different guidance receptors regulate the motility of the axonal growth cone, a number of common themes have emerged. We review recent insights into how specific receptors for each of these guidance cues engage downstream regulators of the growth cone cytoskeleton to control axon guidance. Vav proteins may primarily promote cell detachment by mediating local Rac-dependent endocytosis of the ephrin-Eph complex and membrane. Adaptation in Xenopus retinal growth cones to Sema3A or netrin-1 involves two processes: A fast desensitization, A
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