How growth cones are steered
 
Growth cone navigation The growth cone detects extrinsic cues and forges ahead to synaptic targets. These cues are surface-bound (7,18,35,37) or soluble (2,23), and they signify attractive and repulsive information for a migrating growth cone, like “Exit Ramp” and “Do Not Enter” signs on roads. As a growth cone travels, it detects multiple cues, and the cues change as a growth cone progresses to it’s destination. The eyes and ears of a growth cone are surface receptors that detect extrinsic cues and trigger changes in cytoskeletal and membrane dynamics that advance and turn the growth cone. These receptors adorn filopodia and lamellipodia, as they reach beyond the growth cone, searching for the environment for cues (11,16). Lamellipodia and filopodia (Video 2)(YouTube videos 3,4,5), especially, can extend 50 µm and more from the growth cone, creating a large search volume around a growth cone (9,16). Microtubule Advance An axon grows as its microtubules and associated organelles advance as the growth cone moves forward. The dynamic actin-based motility of the growth cone directs microtubule advance via interactions of distal microtubule tips in the P-domain with actin filament bundles and adhesion sites (Figure 4). Microtubules align with actin bundles, and dynamic microtubule tips advance and shrink along the filament bundles (3,6,22). Microtubule tips approach but do not extend beyond the substrate adhesive sites at the leading margin (Figure 5). Thus, like a tugboat towing ships into a harbor, actin filament bundles and their adhesive anchors at the growth cone front direct the advance of the axonal cytoskeleton and its cargo. This machinery for advancing the growth cone and axonal microtubules is the focus of directive signals triggered by the extrinsic cues that guide growth cone migration. How Growth Cones are Steered by Guidance Cues Although microtubules and actin filaments are both targets of guidance cue signals, the actin filament machinery is the more common target (34). Guidance receptors are linked to molecular switches, notably Rho GTPases, that activate signaling pathways to regulate actin-binding and microtubule-binding proteins that control the dynamic organization and distribution of actin filaments and microtubules. The formation of substrate adhesions and plasma membrane dynamics at the leading growth cone margin are also downstream targets of Rho GTPases (28,34). Repulsive guidance cues like ephrinA’s and Semaphorin3A switch on the GTPase RhoA, which reduces growth cone protrusion and adhesion, promotes actin depolymerization and stimulates myosin II contraction (Video 3)(Youtube videos 2,5). In contrast, attractive cues like neurotrophins and netrin switch off RhoA and switch on GTPases Rac1 and Cdc42, which promote actin filament polymerization and dynamic formation of substrate adhesions (27,32,34,36)(YouTube videos 3,4). Because growth cones simultaneously encounter positive and negative cues, the activities of Rho GTPases fluctuate through integration of the signals triggered by attractive and repulsive guidance cues (28,29,31,34,37) (Figure 6). Cytoplasmic Ca flux is another important signaling element (12,17,19,36). Finally, changing protein activity in growth cones may involve local protein synthesis via translational control of specific mRNAs transported to growth cones from the cell body (but also see 38) . Axonal guidance cues are expressed on surfaces as homogenous displays, isolated islands or gradients, and are expressed as soluble gradients (1,2,7,9,20,23,35). Migrating growth cones encounter asymmetries in the distributions of these bound and soluble guidance cues, and consequently, their intracellular signaling activities are asymmetrically distributed in growth cones. Thus, when a growth cone detects a Semaphorin3A-rich surface to one side, the loss of actin and substrate adhesion at that side turns the growth cone away (Video 4), and when a growth cone encounters higher levels of netrin or other attractive cue to one side, actin polymerization will be stimulated in that side and the growth cone advances readily towards the attractive cue (39)(Video 5)(Youtube video 6).http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714171/?tool=pubmedLetourneau_PDF_files.htmlLetourneau_PDF_files.htmlhttp://rstb.royalsocietypublishing.org/content/361/1473/1513.longLetourneau_PDF_files.htmlVideos.htmlYouTube_videos.htmlLetourneau_PDF_files.htmlFigures.htmlLetourneau_PDF_files.htmlFIgures-2.htmlLetourneau_PDF_files.htmlhttp://jcs.biologists.org/cgi/content/full/114/15/2713http://jcs.biologists.org/cgi/content/full/114/15/2713Letourneau_PDF_files.htmlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1664662/?tool=pubmedVideos.htmlYouTube_videos.htmlLetourneau_PDF_files.htmlYouTube_videos.htmlLetourneau_PDF_files.htmlFIgures-2.htmlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474798/?tool=pubmedLetourneau_PDF_files.htmlhttp://www.nature.com/emboj/journal/v26/n16/abs/7601808a.htmlLetourneau_PDF_files.htmlLetourneau_PDF_files.htmlVideos.htmlLetourneau_PDF_files.htmlVideos.htmlYouTube_videos.htmlshapeimage_3_link_0shapeimage_3_link_1shapeimage_3_link_2shapeimage_3_link_3shapeimage_3_link_4shapeimage_3_link_5shapeimage_3_link_6shapeimage_3_link_7shapeimage_3_link_8shapeimage_3_link_9shapeimage_3_link_10shapeimage_3_link_11shapeimage_3_link_12shapeimage_3_link_13shapeimage_3_link_14shapeimage_3_link_15shapeimage_3_link_16shapeimage_3_link_17shapeimage_3_link_18shapeimage_3_link_19shapeimage_3_link_20shapeimage_3_link_21shapeimage_3_link_22shapeimage_3_link_23shapeimage_3_link_24shapeimage_3_link_25shapeimage_3_link_26shapeimage_3_link_27shapeimage_3_link_28shapeimage_3_link_29shapeimage_3_link_30