, 2009 and Kabayama et al., 2011), stimulus dependent endocytosis in the growth cone has mostly been shown to occur through clatherin mediated endocytosis (CME). CME is a known regulator of the surface buy Alpelisib expression of receptors involved in outgrowth and clatherin activity is necessary for both guidance and desensitization to guidance cues (Tojima et al., 2011). CME occurs downstream of Ca2+ elevation and is an essential mediator of Ca2+ induced chemorepulsion (Tojima et al., 2010). It is highly likely that CME is one of the first downstream events following Ca2+ elevation as it precedes any cytoskeletal remodeling associated with the turning response (Tojima et al., 2010). Recently,

it has become evident that asymmetric CME is essential for mediating guidance responses within the growth cone during repulsion. During myelin-associated glycoprotein (MAG) induced repulsion, there is a rapid spatial remodeling of cell adhesion components, including the surface receptor β1-integrin, with their distribution shifting toward the side that is opposite to the one stimulated by MAG (Hines et al., 2010). This is achieved through CME surface removal of the β1-integrin on the side of the growth cone undergoing repulsion. CME also occurs following local application of Semaphorin 3A (Tojima et al., 2010). Furthermore, local inhibition of CME through application of the clatherin inhibitor MDC was sufficient tuclazepam to

cause an attractive guidance response (Tojima et al., 2010). While these data support the selleck compound notion that asymmetric alteration of the balance of exo- and endocytosis can elicit growth cone steering, they do not directly demonstrate that endocytosis is sufficient to induce growth cone repulsion. An ultimate test for a sufficient role of local endocytosis in growth cone repulsion would require techniques that can directly and specifically elicit local endocytosis to examine the growth cone’s response. It has become increasingly

clear that directional growth cone motility is controlled by a combination of mechanisms. While each of these processes regulates distinct sets of cellular activities, they must work in concert to enable the growth cone to respond to environmental signals. Remarkably, there is a substantial amount of crosstalk among different pathways (Figure 3). For example, while the actin cytoskeleton plays a predominant role in motility by providing the major force behind cell protrusions, it also has been shown to spatially regulate microtubule dynamics and membrane recycling. This in turn would affect the delivery and retrieval of migration-relevant molecules, whose downstream targets are ultimately the actin cytoskeleton. Similarly, adhesions are both upstream and downstream of signals from the actin cytoskeleton, microtubules, and membrane recycling pathways (Kolodkin and Tessier-Lavigne, 2011 and Myers et al., 2011).