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“Neural connections form during development when neurons extend stalk-like axonal appendages that actively explore their environment, seeking specific signals that will guide them to their targets. Work over the past 20 years has identified a number of these extracellular signals, revealing that specific attractive and repulsive guidance cues control

the cytoskeletal and adhesive machinery necessary for axon elongation (Kolodkin and Tessier-Lavigne, 2011). More recently, transmembrane Roxadustat cell line receptors and intracellular signaling molecules have been found for many of these guidance cues, providing a further understanding of the molecular biology of axon guidance (Kolodkin and Tessier-Lavigne, 2011 and Bashaw and Klein, 2010). Yet, these fundamental discoveries have also

raised important new questions regarding the biochemical mechanisms that enable growing axons to choose among this diverse array of guidance information, much of which is presented in concert, to precisely navigate to their targets. Semaphorins (Semas) are among the largest families of axon guidance cues and are best known for their ability to sculpt the nervous system by serving as axonal repellents (Kolodkin and Tessier-Lavigne, 2011). Semas exert their repulsive effects by disassembling find more the actin and microtubule cytoskeletal elements necessary for axonal extension, as well as by disrupting the adhesive interactions between an axon and its substrate (Hung and Terman, 2011). Semas utilize Plexin receptors to exert their cell biological effects, and recently a number of signaling molecules have been identified that mediate Sema/Plexin effects on the

cytoskeleton (Zhou et al., 2008 and Bashaw and Klein, 2010), including an actin disassembly factor, Mical (Hung et al., 2010 and Hung et al., 2011). Interestingly, Plexins also directly associate with small GTP-binding proteins and contain a GTPase activating protein (GAP) domain within their cytoplasmic portions click here (Rohm et al., 2000, Vikis et al., 2000, Driessens et al., 2001, Hu et al., 2001, Oinuma et al., 2004, He et al., 2009, Tong et al., 2009 and Wang et al., 2012). These observations have provided a direct link between Semas/Plexins and small GTP-binding proteins, which are key regulators of cytoskeletal dynamics and cell adhesion (Hall and Lalli, 2010). Indeed, in vitro work has indicated that Plexins exert repulsive/de-adhesive effects on growing axons by employing their Ras/Rap GAP activity to inhibit Integrin-dependent axon-substrate adhesion (Oinuma et al., 2004, Oinuma et al., 2006, Toyofuku et al., 2005, Uesugi et al., 2009, Tong et al., 2009 and Wang et al., 2012). Growing evidence also indicates that the repulsive effects of axon guidance cues can be silenced and even turned into attraction by raising the levels of specific signaling molecules like cyclic nucleotides.