How growth cones migrate
 
Axon elongation At the tip of a growing axon the microtubule bundle loosens and splays, as the axon expands into a growth cone (6), which may be 5-20 µm wide (Figure 3). The actin network beneath the plasma membrane is expanded, filling the growth cone with a 3-D network of interconnected actin filaments and filament bundles. Microtubule tips project from the central growth cone, called the C-domain, into the front margin, the P-domain, and terminate in the actin network (6,10,21). When viewed live, this cytoskeletal network is highly dynamic. Microtubule ends grow and shrink, through a flux of subunits at the tips. Actin filaments polymerize rapidly at the leading edge, pushing it forward as finger-like filopodia and flattened lamellipodia (Video 1). This actin network also slides back from the leading margin, pulled by myosin II motors interspersed throughout the actin network (4,11,29). The actin network contracts and disassembles close behind the leading margin, releasing actin subunits to reassemble at the front and sustain the leading margin’s advance. Regulatory Proteins The exuberant dynamics of the growth cone cytoskeleton are orchestrated by microtubule- and actin-binding proteins that control all aspects of assembly, disassembly, stability and interactions of microtubules and actin filaments. Growth cones contain a rich mix of these regulatory proteins, whose activities determine growth cone behaviors (11,14,32,33). These microtubule- and actin-binding proteins, in turn, are regulated by cytoplasmic signaling pathways that are downstream from both intrinsic regulatory signals and extrinsic molecular cues that steer growth cone migration. Growth Cone Advance The axon elongates as actin polymerization advances the growth cone leading margin and as microtubule polymerization and stabilization yields a net increase in microtubule advance (10,21). A key element that links these two activities is growth cone adhesion to nearby cells and extracellular materials (3). The surfaces of newly formed filopodia and lamellipodia bear adhesion molecules that bind in homophilic and heterophilic combinations with ligands on adjacent surfaces. These bonds stabilize the newly extended protrusions, and initiate molecular assemblies that link newly formed actin filaments to adhesive sites (11,20,24,37). This tethering of actin filaments at adhesive sites counteracts the retrograde flow that otherwise pulls actin rearward toward disassembly, and provides space into which microtubules can advance, along with organelles and axonal components. Myosin II motors in the actin network tug on the adhesive sites and exert tension that can pull the growth cone forward (4,11). At the back of a growth cone adhesion diminishes, actin polymerization wanes, and myosin II motors trim the broad growth cone into the cylindrical profile of the axon. A few filopodia may remain along the axon as remnants of the dynamic leading edge. New axonal branches can arise at a growth cone when the advance of microtubules and associated organelles is segregated into more than one bundle within the growth cone C- or P- domains (6,8). Letourneau_PDF_files.htmlFigures.htmlLetourneau_PDF_files.htmlhttp://jcb.rupress.org/cgi/content/full/jcb.200203038/DC1Videos.htmlLetourneau_PDF_files.htmlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525020/?tool=pubmedhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714171/?tool=pubmedLetourneau_PDF_files.htmlLetourneau_PDF_files.htmlLetourneau_PDF_files.htmlLetourneau_PDF_files.htmlhttp://www.ncbi.nlm.nih.gov/pubmed/19118212?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=4http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2595147/?tool=pubmedLetourneau_PDF_files.htmlLetourneau_PDF_files.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_15