Update articleIntracellular signaling and membrane trafficking control bidirectional growth cone guidance
Highlights
► Ca2+ release from the endoplasmic reticulum mediates attractive axon guidance. ► Ca2+ signals without Ca2+ release favor repulsive axon guidance. ► Exocytic membrane trafficking drives Ca2+-induced growth cone attraction. ► Endocytic membrane trafficking drives Ca2+-induced growth cone repulsion. ► The imbalance between exocytosis and endocytosis dictates bidirectional axon guidance.
Introduction
Growth cones, motile amoeboid structures at the tips of growing axons, migrate along specific routes to form precise neuronal networks. On their way to final targets, growth cones change their direction of migration in response to extracellular gradients of “guidance cues” secreted by their intermediate and final targets (Chao et al., 2009, O’Donnell et al., 2009, Tessier-Lavigne and Goodman, 1996). A large number of guidance cues have been identified so far, and most of them can act as bidirectional cues. For example, the same guidance cue can attract or repel growth cones depending on the context, such as the type of growth cones, their developmental stages, and the surrounding extracellular microenvironments. Because individual growth cones must choose different routes to their final targets, it is logical that guidance cues act bidirectionally. Interestingly, to pass through an intermediate target, growth cones need to reverse their responsiveness to the cue secreted by the intermediate target from attraction to repulsion (Shewan et al., 2002). These findings clearly indicate that the polarity of growth cone guidance with respect to the cue must be determined individually by growth cones through their intracellular signaling and driving mechanisms.
Accumulating evidence has revealed the essential roles of intracellular second messengers, such as Ca2+, inositol 1,4,5-trisphosphate (IP3), cyclic AMP (cAMP), and cyclic GMP (cGMP), in determining the polarity of growth cone guidance (Gomez and Zheng, 2006, Henley and Poo, 2004, Tojima et al., 2011). Furthermore, recent studies demonstrate that exocytic and endocytic membrane trafficking within the growth cone drives growth cone guidance downstream of second messengers (Akiyama and Kamiguchi, 2010, Hines et al., 2010, Itofusa and Kamiguchi, 2011, Tojima et al., 2007, Tojima et al., 2010, Tojima et al., 2011). In this Update Article, I summarize the recent developments in the understanding of the signaling and driving mechanisms underlying bidirectional growth cone guidance, focusing especially on our recent work.
Section snippets
Ca2+ signaling in bidirectional growth cone guidance
Pioneering work in the 1980s and 1990s has revealed that cytosolic Ca2+ signals are critically involved in the regulation of axon outgrowth and growth cone collapse (Kater and Mills, 1991). With the use of an in vitro growth cone turning assay, developed originally by Gundersen and Barrett (1979), subsequent work in the 2000s has demonstrated the essential role of Ca2+ signals in growth cone guidance (Akiyama et al., 2009, Henley et al., 2004, Hong et al., 2000, Li et al., 2005, Togashi et al.,
Cyclic nucleotide signaling in bidirectional growth cone guidance
Earlier studies showed that pharmacological manipulation of cytosolic cAMP signaling could switch the direction of Ca2+-dependent growth cone turning induced by guidance cues (Song and Poo, 1999). For example, growth cone attraction induced by netrin-1 (Ming et al., 1997), NGF (Ming et al., 1999), BDNF (Song et al., 1997), and MAG (Tojima et al., 2007) was converted to repulsion by bath application of the membrane-permeable cAMP antagonist Rp-cAMPS. Growth cone repulsion induced by MAG was also
Membrane transport and exocytosis for growth cone attraction
What mechanisms act downstream of Ca2+ signals to drive bidirectional growth cone guidance? Accumulating evidence indicates that cytoskeletal and adhesion dynamics in growth cones are involved in attractive and repulsive growth cone guidance in the following manner: the growth cone turns preferentially toward the side with cytoskeletal assembly and increased adhesion and away from the side with cytoskeletal disassembly and decreased adhesion (Dent et al., 2011, Lowery and Van Vactor, 2009,
Endocytosis for growth cone repulsion
Next, we focused on the mechanisms of growth cone repulsion. Previous findings showed that endocytosis occurs during growth cone collapse induced by bath application of repulsive guidance cues Sema3A (Fournier et al., 2000), Slit2 (Piper et al., 2006), and ephrins (Mann et al., 2003). On the basis of these findings, we tested whether growth cone repulsion is driven by spatial asymmetry in endocytosis across the growth cone (Tojima et al., 2010). Clathrin-mediated endocytosis is a major process
Imbalance between exocytosis and endocytosis dictates growth cone guidance
We further tested whether direct local manipulation of exocytosis or endocytosis can trigger growth cone turning (Tojima et al., 2010). Even in the absence of guidance cues, local application of the endocytosis inhibitor monodansylcadarverine on one side of the growth cone with a glass pipette triggered growth cone turning toward the side with lower endocytic activity. Similarly, local application of the exocytosis stimulator α-latrotoxin caused growth cone turning toward the side with higher
Hypothetical model for growth cone steering
As described above, we and others have developed a novel model in which exocytic and endocytic membrane trafficking drive bidirectional growth cone guidance (Fig. 2). It is also well known that cytoskeletal and adhesion dynamics are critical regulators of growth cone guidance (Dent et al., 2011, Lowery and Van Vactor, 2009, Myers et al., 2011, Vitriol and Zheng, 2012). How does the membrane trafficking system cooperate with cytoskeletal and adhesion dynamics to steer the growth cone? The
Conclusions and perspectives
Recent advances in growth cone research have revealed a series of intracellular signaling and mechanical events that translate extracellular guidance signals into bidirectional growth cone turning. Notably, we and others have provided novel evidence that bidirectional growth cone turning is driven by polarized membrane trafficking downstream of Ca2+ signals. However, the vast majority of these studies have been conducted using in vitro assays. Therefore, one of the important challenges for
Acknowledgements
I am deeply grateful to Hiroyuki Kamiguchi (Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute) for his support, encouragement, and helpful discussion. I also thank Rurika Itofusa for her critical reading of this manuscript. My work is supported in part by Grants-in-Aid for Scientific Research from the MEXT and JSPS (16700297, 18700332, 20700302, 22700353, and 23110005), and the JST PRESTO program to T.T.
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