Trends in Neurosciences
ReviewCalcium signaling in axon guidance
Introduction
For the brain to be wired correctly during development axons must navigate appropriately to their targets, often over long distances. Axons achieve this feat by detecting and responding appropriately to numerous molecular and physical guidance cues in their local environment, usually via the growth cone [1]. This includes guidance by growth through permissive conduits, by substrate-bound guidance cues, or by gradients of diffusible cues. Several molecular guidance cue families involved in axon guidance have been identified including the netrins, semaphorins, ephrins, slits, neurotrophins, Wnts, and some morphogens 2, 3. These cues are detected by receptors on the axon surface, which then activate a variety of downstream signaling pathways to cause axon turning and/or changes in growth rate [4].
One of the most crucial components of these pathways is calcium 5, 6, 7, 8. Calcium concentrations in growth cones are regulated both by calcium influx through the plasma membrane and by release from intracellular calcium stores 9, 10 (see Glossary). A calmodulin-dependent protein kinase II (CaMKII)ācalcineurin (CaN) switch often initiates either an attractive (turning towards the highest guidance cue concentration) or repulsive (turning away from the highest guidance cue concentration) response to these intracellular calcium elevations [8]. These responses are effected via the regulation of cytoskeletal components, such as microtubules and actin filaments 11, 12, 13, 14, 15, and by membrane dynamics, including vesicle trafficking 16, 17, 18. In the past few years many new insights have emerged regarding the central and multifaceted roles of calcium in mediating axon growth and guidance. We review here some of these developments, focusing particularly on new mechanisms for producing and mediating calcium elevations, the involvement of calcium in the attraction/repulsion switch, how calcium modulates growth cone motility, and the role of calcium in guidance by Wnt5a.
Section snippets
Mechanisms of calcium entry
The spatial distribution and level of intracellular calcium is crucial for axon guidance [19], and regulation of this distribution begins with calcium entry into the growth cone. Methods of entry particularly important for axon guidance include voltage-dependent calcium channels (VDCCs), release of intracellular calcium stores, and store-operated calcium entry (SOCE) from extracellular sources (Figure 1). The most important VDCCs for growth cone turning are the L-type Ca2+ channels 20, 21.
Role of calcium in turning
A turning response requires asymmetric deployment of signaling molecules between the two sides of the growth cone. Zheng [44] used focal laser-induced photolysis (FLIP) of caged calcium to generate a spatially restricted elevation of intracellular calcium concentration on one side of the growth cone. This asymmetric calcium elevation is sufficient to cause growth cone turning; however, the direction is dependent on the steepness of the calcium gradient and background calcium concentrations [44]
Downstream effects of calcium
Although a molecular switch mediated by CaMKII and CaN likely determines the growth cone response to intracellular calcium distributions, it is downstream effectors which induce membrane trafficking and cytoskeletal changes that create this response 16, 17, 48. Repulsive guidance cues usually induce asymmetric endocytosis [17], whereas attractive cues induce asymmetric exocytosis [50]. Notably, these responses are not merely the same response with the sign reversed; attraction to the left of a
Calcium, motility, and growth rate
The role of calcium signaling in overall growth cone motility is less well understood than its role in turning. Calcium signaling has an effect on the growth rate of growth cones, first characterized as a narrow extracellular calcium concentration range favorable for growth 43, 60, 61, 62. Surprisingly, calcium transients 63, 64 and calcium entry through mechanosensitive channels slow axon growth, whereas calcium release from ER stores enhances growth [41]. The relation between calcium
Concluding remarks
Although Ca2+ has long been implicated as a second messenger in growth cone turning, it is only over the past few years that the precise distributions and mechanisms for attraction and repulsion have been elucidated. Many different mechanisms for intracellular Ca2+ elevation have been discovered, including release from ER stores (CICR and IICR) and entry from extracellular sources (CRAC, SOCE, and voltage-sensitive Ca2+ channels) 22, 33, 34, 38. A complex pathway which interprets these
Acknowledgments
We gratefully acknowledge support from National Health and Medical Research Council (NHMRC) Project Grant 1043044, and thank Beth Kita and Rowan Tweedale for providing helpful feedback on earlier versions.
Glossary
- Axon guidance by growth rate modulation
- a type of chemotactic movement whereby axon guidance up the gradient is mediated not by turning, but instead by the axon taking larger steps when it is pointed up the gradient than when it is pointed down the gradient; [67] for more details.
- Calcium-induced calcium release (CICR)
- the release of calcium from intracellular stores in response to rising calcium concentration (i.e., a positive feedback process).
- Calcium release-activated channel (CRAC)
- calcium
References (93)
Growth cone chemotaxis
Trends Neurosci.
(2008)- et al.
Signaling mechanisms of non-conventional axon guidance cues: the Shh, BMP and Wnt morphogens
Curr. Opin. Neurobiol.
(2013) - et al.
Directional guidance of nerve growth cones
Curr. Opin. Neurobiol.
(2006) Calcium-induced release of calcium regulates differentiation of cultured spinal neurons
Neuron
(1991)Localized membrane depolarizations and localized calcium influx during electric field-guided neurite growth
Neuron
(1992)Asymmetric clathrin-mediated endocytosis drives repulsive growth cone guidance
Neuron
(2010)DCC-dependent phospholipase C signaling in netrin-1-induced neurite elongation
J. Biol. Chem.
(2006)Calcium mediates bidirectional growth cone turning induced by myelin-associated glycoprotein
Neuron
(2004)Expression of STIM1 in brain and puncta-like co-localization of STIM1 and ORAI1 upon depletion of Ca2+ store in neurons
Neurochem. Int.
(2009)- et al.
Phosphatidylinositol 3-kinase facilitates microtubule-dependent membrane transport for neuronal growth cone guidance
J. Biol. Chem.
(2010)
Calcium and cAMP levels interact to determine attraction versus repulsion in axon guidance
Neuron
A CaMKII/calcineurin switch controls the direction of Ca2+-dependent growth cone guidance
Neuron
Semaphorin3A facilitates axonal transport through a local calcium signaling and tetrodotoxin-sensitive voltage-gated sodium channels
Biochem. Biophys. Res. Commun.
Netrin-1 is required for commissural axon guidance in the developing vertebrate nervous system
Cell
Rho GTPases in growth cone guidance
Curr. Opin. Neurobiol.
Ca2+/calmodulin dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation
Biochem. Biophys. Res. Commun.
SDF-1-induced intracellular calcium transient involves Rho GTPase signalling and is required for migration of hematopoietic progenitor cells
Biochem. Biophys. Res. Commun.
Filopodial calcium transients regulate growth cone motility and guidance through local activation of calpain
Neuron
Developmental changes in the regulation of calcium-dependent neurite outgrowth
Biochem. Biophys. Res. Commun.
Characterization of spontaneous calcium transients in nerve growth cones and their effect on growth cone migration
Neuron
Cyclic nucleotide-dependent switching of mammalian axon guidance depends on gradient steepness
Mol. Cell. Neurosci.
Calcium-induced synergistic inhibition of a translational factor eEF2 in nerve growth cones
Biochem. Biophys. Res. Commun.
Brain-derived neurotrophic factor enhances the basal rate of protein synthesis by increasing active eukaryotic elongation factor 2 levels and promoting translation elongation in cortical neurons
J. Biol. Chem.
Elongation factor-2 kinase: immunological evidence for the existence of tissue-specific isoforms
FEBS Lett.
Bistability in the Ca2+/calmodulin-dependent protein kinase-phosphatase system
Biophys. J.
Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration
Mol. Cell. Neurosci.
Intracellular signaling and membrane trafficking control bidirectional growth cone guidance
Neurosci. Res.
New perspectives in cyclic AMP-mediated axon growth and guidance: the emerging epoch of Epac
Brain Res. Bull.
Protein kinase C and integrin-linked kinase mediate the negative axon guidance effects of Sonic hedgehog
Mol. Cell. Neurosci.
Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism
Neuron
Molecular mechanisms of axon guidance
Science
Calcium signaling in neuronal motility
Annu. Rev. Cell Dev. Biol.
Filopodial calcium transients promote substrate-dependent growth cone turning
Science
Second messenger pas de deux: the co-ordinated dance between calcium and cAMP
Sci. STKE
The interdependent roles of Ca2+ and cAMP in axon guidance
Dev. Neurobiol.
Calcium influx alters actin bundle dynamics and retrograde flow in Helisoma growth cones
J. Neurosci.
Axon guidance by growth cones and branches: common cytoskeletal and signaling mechanisms
Neuroscientist
Regulation of growth cone actin filaments by guidance cues
J. Neurobiol.
Ca2+-dependent regulation of rho GTPases triggers turning of nerve growth cones
J. Neurosci.
An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance
Nat. Neurosci.
Asymmetric endocytosis and remodeling of beta1-integrin adhesions during growth cone chemorepulsion by MAG
Nat. Neurosci.
Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone
Nat. Neurosci.
Spatial and temporal second messenger codes for growth cone turning
Proc. Natl. Acad. Sci. U.S.A.
Calcium signalling in the guidance of nerve growth by netrin-1
Nature
Cyclic AMP/GMP-dependent modulation of Ca2+ channels sets the polarity of nerve growth-cone turning
Nature
Control of neuronal growth cone navigation by asymmetric inositol 1,4,5-trisphosphate signals
Sci. Signal.
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2023, Seminars in Cell and Developmental BiologyCitation Excerpt :Filopodial sensing and signal transduction most likely originate at the filopodial tip, where receptors and specialized signal transduction machinery localize [3,57,58]. Calcium signals have been observed in filopodia of neuronal growth cones [3,30,59] and are discussed in Section 4; it seems plausible that similar signaling occurs in growth cone-like structures at the leading edge of migrating cells. Similar to other migrating cell types, migrating facial branchiomotor neurons have been proposed to signal via actin regulators and integrate signals from several filopodia [57,60].
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2018, iScienceCitation Excerpt :Guidance of axons in vivo in the model system of the developing tadpole has been addressed in Borisyuk et al. (2014), Roberts et al. (2014), and Davis et al. (2017), and a general simulation tool for modeling the trajectories of axons in gradients applicable to a variety of situations was presented in Krottje and van Ooyen (2007). A surprising experimental finding is that axonal responses to gradients can switch from attraction to repulsion depending on the levels of both calcium and cAMP in the growth cone (reviewed in Song and Poo (2001) and Sutherland et al. (2014)). Intriguingly the signaling pathways underlying this switch bear strong similarity with the pathways involved in switching between long-term potentiation and long-term depression at a synapse (Graupner and Brunel, 2010).