In vivo regulation of axon extension and pathfinding by growth-cone calcium transients

Abstract

Growth cones at the tips of extending neurites migrate through complex environments in the developing nervous system and guide axons to appropriate target regions using local cues. The intracellular calcium concentration ([Ca2+]i) of growth cones correlates with motility in vitro, but the physiological links between environmental cues and axon growth in vivo are unknown. Here we report that growth cones generate transient elevations of [Ca2+]i as they migrate within the embryonic spinal cord and that the rate of axon outgrowth is inversely proportional to the frequency of transients. Suppressing Ca2+ transients by photorelease of a Ca2+ chelator accelerates axon extension, whereas mimicking transients with photorelease of Ca2+ slows otherwise rapid axonal growth. The frequency of Ca2+ transients is cell-type specific and depends on the position of growth cones along their pathway. Furthermore, growth-cone stalling and axon retraction, which are two important aspects of pathfinding, are associated with high frequencies of Ca2+ transients. Our results indicate that environmentally regulated growth-cone Ca2+ transients control axon growth in the developing spinal cord.

Neuregulin1/ErbB4-induced migration in ST14A striatal progenitors: calcium-dependent mechanisms and modulation by NMDA receptor activation

“…The role of increases of the cytosolic calcium concentration in controlling cell motility has been reported in various cell types ranging from fibroblasts to immature neurons [39,40]. Neuronal precursors and post-migratory neurons in the fetal cerebrum and the early postnatal cerebellum exhibit spontaneous Ca 2+ transients [41,42], suggesting that the role of Ca 2+ transients in development may be constantly remodelled by internal programs and extracellular cues.…”

High affinity binding of long-chain polysialic acid to antibody, and modulation by divalent cations and polyamines

“…Possible effects of calcium are intriguing as it is involved in several adhesion-related events in the central nervous system: Ca 2+ affects the conformation, aggregation and refolding transitions of ependymin (a cell-adhesion related molecule associated in neural plasticity) (Ganss and Hoffmann, 1993). Also Ca 2+ binding to sialic acids facilitates fibrinogen monomer aggregation in fibrin assembly (Dang et al, 1989) and Ca 2+ transients were shown to control in vivo regulation of axon extension and growth-cone path finding (Gomez and Spitzer, 1999)-a phenomenon also associated with NCAM-PSA. Although the extra-cellular Ca 2+ concentration in brain is normally low, local concentrations may differ by several orders of magnitude due to gradients, mirroring intracellular transients (Nicholson, 1980).…”

“…Calcium entry is also shown to regulate NCAM isoform expression and polysialylation in the developing muscle (Rafuse and Landmesser, 1996). Interestingly, the polysialic acid moiety of the NCAM was recently shown to be involved in the guidance of retinal axons (Monnier et al, 2001), an event also controlled by Ca 2+ (Gomez and Spitzer, 1999). As a hygroscopic salt, Ca 2+ could double the effective hydration volume of PSA-a property that is considered sufficient to explain the role of PSA in NCAM function (Troy, 1992).…”

Calcium signaling in axon guidance

“…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].…”