EQ was obtained by using EQ = brain weight/0.12 (body weight)0.67 (Butti et al., 2009). We thank A.D. (Bud) Craig for his relecture of our revision and insightful suggestions. We thank J. Schramm, Z. Aschrafi, O. Groht, K. Piasecka, K. Bogdanova, and S. Sànchez-Ancora for their excellent technical assistance. We thank A. Bartels, M. Herdener,

R. Diogo, and C. Kayser for their feedback on a previous version of this manuscript. “
“The ability of growing axons to accurately locate targets during development or regeneration is critical for the formation of correct neural circuits. Growing axons are tipped with growth cones, which detect distributions of molecular guidance cues in their environment. A key mechanism for guidance is chemotaxis, whereby growth cones detect and respond to concentration gradients of these cues (Tessier-Lavigne and Goodman, 1996, Song and Poo, 2001, Chilton, R428 mouse 2006, Mortimer et al., 2008 and O’Donnell et al., 2009). In a gradient, growth cone receptors closer to the source of the guidance cue are bound more frequently, leading to asymmetric intracellular signaling events mediated by second messengers. This leads to polarization of the growth cone, and a turn toward (attraction) ABT 263 or away (repulsion) from the

source of the guidance cue. Calcium signals mediate both growth cone turning and outgrowth (Cohan et al., 1987). Binding of the guidance cue to receptors on the growth cone can trigger the influx of calcium into the cytoplasm from calcium stores in the endoplasmic reticulum by activation of ryanodine receptors or inositol-1,4,5-triphophate receptors, or from extracellular sources via voltage-dependent calcium enough channels (Berridge et al., 2003) and transient receptor potential (TRP) calcium channels (Henle et al., 2011). Blocking calcium entry through membrane-bound or ryanodine channels can abolish the guidance response, or even switch a normally attractive turning response to a guidance

cue to repulsion (Hong et al., 2000). Guidance cues that are normally repulsive do not usually result in calcium release from the endoplasmic reticulum and therefore only result in a shallow intracellular calcium gradient (Tojima et al., 2011). Thus, under normal conditions, a steep intracellular calcium gradient in response to a guidance cue gradient is likely to result in attraction, whereas a shallow intracellular calcium gradient is likely to result in repulsion (Hong and Nishiyama, 2010). Calcium is quickly buffered by calmodulin, binding to form a calcium/calmodulin complex (Faas et al., 2011). Calcium/calmodulin has many effector molecules. Two of particular relevance for growth cone turning are calcium/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN).