Key Points
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During neural development, graded distribution of extracellular cues in the microenvironment causes asymmetric generation of second messengers across the growth cone in order to guide the axon along its correct path. Asymmetrically generated Ca2+ signals are sufficient to initiate growth cone turning toward (attraction) or away from (repulsion) the side with higher Ca2+ concentrations.
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Gating of differential sets of Ca2+ channels, which are regulated counteractively by cyclic AMP and cyclic GMP, can be responsible for switching between growth cone attraction and repulsion. We propose that high-amplitude Ca2+ elevation involving Ca2+ release from the endoplasmic reticulum mediates attractive guidance, whereas low-amplitude Ca2+ influx that does not trigger substantial Ca2+ release from the endoplasmic reticulum mediates repulsive guidance.
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Shallow concentration gradients of guidance cues can shape growth cone Ca2+ signals for precise navigational responses. This process may depend on second messenger networks including positive-feedback augmentation between Ca2+ and cyclic AMP.
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Repulsive Ca2+ signals cause asymmetric clathrin-mediated endocytosis across the growth cone with more endocytosis on the side with elevated Ca2+. Attractive Ca2+ signals promote centrifugal transport of membrane vesicles and their subsequent exocytosis mediated by vesicle-associated membrane protein 2 on the side with elevated Ca2+.
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We propose that asymmetric membrane trafficking is an early and instructive step in the initiation of growth cone turning. Localized imbalance between endocytosis and exocytosis may trigger redistribution of adhesion molecules, cytoskeletal components and bulk membrane, which would potentiate asymmetric traction and protrusion forces essential for turning.
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The growth cone in complex environmental terrain in vivo must integrate multiple guidance signals simultaneously to navigate with high fidelity. Spatiotemporally regulated interactions among Ca2+ and cyclic nucleotides potentially have crucial roles in this integration process, which will need to be scrutinized by quantitative imaging of multiple second messengers in navigating growth cones.
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.
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Acknowledgements
We apologize to investigators whose work could not be cited owing to space limitations. The authors' work is supported by the RIKEN Brain Science Institute (H.K.), grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (H.K. and T.T.), the Japan Science and Technology Agency PRESTO program (T.T.), funding from the US National Institutes of Health (J.R.H.), and a John M. Nasseff, Sr. Career Development Award in Neurologic Surgery Research from the Mayo Clinic, USA (J.R.H).
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Glossary
- Local augmentation
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A theoretical reaction of chemotactic cells for gradient sensing, in which signals are augmented locally in the cellular area containing higher receptor occupancy.
- Global inhibition
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Another theoretical reaction for gradient sensing. The locally augmented signals can be further isolated by spreading antagonistic signals over the whole cell.
- Adaptation
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The ability of a growth cone to readjust its sensitivity over a wide range of guidance cue concentrations during long-distance chemotaxis.
- Early endosome
-
An intracellular membrane compartment where endocytosed molecules are sorted and directed to the plasma membrane for recycling or to lysosomes for degradation. Early endosomes can also serve as platforms where internalized receptors generate signals.
- CDC42 and RAC1
-
Rho-family GTPases that link extracellular signals to cytoskeletal rearrangements. RAC1 and CDC42 can, for example, promote actin assembly through their major effector actin-related protein 2 (ARP2)–ARP3 complex.
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Tojima, T., Hines, J., Henley, J. et al. Second messengers and membrane trafficking direct and organize growth cone steering. Nat Rev Neurosci 12, 191–203 (2011). https://doi.org/10.1038/nrn2996
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DOI: https://doi.org/10.1038/nrn2996
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