Disease relevance of Growth Cones

• CALI of myosin-V in growth cones of chick dorsal root ganglion neurons resulted in rapid filopodial retraction [1].
• LIM kinase 1 (LIMK1) controls important cellular functions such as morphogenesis, cell motility, tumor cell metastasis, development of neuronal projections, and growth cone actin dynamics [2].
• Pertussis toxin specifically inhibits growth cone guidance by a mechanism independent of direct G protein inactivation [3].
• The axonal surface glycoproteins neuronglia cell adhesion molecule (NgCAM) and axonin-1 promote cell-cell adhesion, neurite outgrowth and fasciculation, and are involved in growth cone guidance [4].
• We suggest that by cleaving a presynaptic protein syntaxin, which is essential in targeting synaptic vesicles as a target SNAP receptor (t-SNARE), neurotoxin C1 of Clostridium botulinum causes growth cone collapse and inhibits axonal growth [5].

Psychiatry related information on Growth Cones

• We propose that profilin may act by forming, during the critical period of cerebellar development, a reserve pool of monomeric actin that can easily be mobilized in cell regions such as growth cones or synaptic junctions where filamentous actin is highly concentrated [6].
• Static and dynamic views of retinal growth cones in this decision region reveal that extensive exploratory behavior and selective retraction of parts of the growing tips of uncrossed fibers, in response to cellular cues at the midline, is a major event in the guidance of these fibers [7].

High impact information on Growth Cones

• Eph receptors transduce short-range repulsive signals for axon guidance by modulating actin dynamics within growth cones [8].
• In addition, expression of a mutant form of ephexin in primary neurons interferes with ephrin-A-induced growth cone collapse [8].
• EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin [8].
• We propose that distinct signals transduced via Trio and Dock act combinatorially to activate Pak in spatially restricted domains within the growth cone, thereby controlling the direction of axon extension [9].
• Previous studies suggested that Roundabout (Robo) is a repulsive guidance receptor on growth cones that binds to an unknown midline ligand [10].

Chemical compound and disease context of Growth Cones

• Pretreatment of ganglion cell axons with C3-transferase, a specific inhibitor of the Rho GTPase, or with Y-27632, a specific inhibitor of the Rho kinase, strongly reduced the collapse rate of retinal growth cones [11].
• Bradykinin-induced collapse of rat pheochromocytoma (PC12) cell growth cones: a role for tyrosine kinase activity [12].
• During neuronal development, netrin and its receptors UNC5 and DCC (deleted in colorectal cancer) guide axonal growth cones in navigating to their targets [13].
• To test this prediction, we reduced the levels of MAP1B-P in neuronal growth cones of dorsal root ganglion cells in culture by inhibiting GSK3beta with lithium [14].
• During hypoxia, nifedipine was more effective in the cell bodies than in the growth cones [15].

Biological context of Growth Cones

• Ligand binding to an Eph receptor results in tyrosine phosphorylation of the kinase domain, and repulsion of axonal growth cones and migrating cells [16].
• Eph receptor tyrosine kinases and their corresponding surface-bound ligands, the ephrins, provide cues to the migration of cells and growth cones during embryonic development [17].
• The results suggest that cell adhesion molecules transduce cell surface events to intracellular signals by modulating the activity of protein tyrosine kinases or phosphatases in axonal membranes to influence cytoskeletal dynamics at the growth cone [18].
• Furthermore, expression of dominant-negative CRMP-2 mutants or knockdown of CRMP-2 message with small-interfering (si) RNA inhibited endocytosis of L1 at axonal growth cones and suppressed axon growth [19].
• Here, genetic analysis in Drosophila is used to demonstrate that mutations in Profilin (chickadee) and Abl (abl) display an identical growth cone arrest phenotype for axons of intersegmental nerve b (ISNb) [20].

Anatomical context of Growth Cones

• Expression of a dominant-negative Plex 1 in sensory neurons blocks Sema3A-induced growth cone collapse [21].
• UNC-6 netrin, a laminin-related protein secreted from neuroglia and neurons along the ventral midline, orients migrating cells and pioneering growth cones on the nematode epidermis [22].
• We report here that SNAP-25 is expressed in axonal growth cones during late stages of elongation and that selective inhibition of SNAP-25 expression prevents neurite elongation by rat cortical neurons and PC-12 cells in vitro and by amacrine cells of the developing chick retina in vivo [23].
• Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin [24].
• Acetylated alpha-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts [25].

Associations of Growth Cones with chemical compounds

• A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion [26].
• Using diffusing latex beads to monitor membrane flow, we find that axonal membrane flows rapidly (7 microns/min) from growth cone to cell body during axon growth and that flow is inhibited by brefeldin A [27].
• Serotonin-containing cell charged with growth cone arrests [28].
• The growth cone response depends on the activation of neuronal nicotinic ACh receptors, requires the presence of extracellular Ca2+, and appears to be mediated by Ca(2+)-calmodulin-dependent protein kinase II [29].
• These results indicate that integrin regulation maintains neuronal growth-cone motility over a broad range of ligand concentrations, allowing axons to invade different tissues during development and regeneration [30].

Gene context of Growth Cones

• Genetic analysis of growth cone guidance in Drosophila: fasciclin II functions as a neuronal recognition molecule [31].
• The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules [32].
• The ubiquitin ligase Rnf6 regulates local LIM kinase 1 levels in axonal growth cones [2].
• Genetic interactions between unc-130 and other guidance genes show that several molecular pathways function in parallel to guide the ventral to dorsal migration of distal tip cells (DTCs) and axonal growth cones in C. elegans [33].
• Moreover, by monitoring the trafficking of a Robo-green fluorescent protein (GFP) fusion in living embryos, we demonstrate that Comm prevents the delivery of Robo-GFP to the growth cone, as predicted by the sorting model [34].

Analytical, diagnostic and therapeutic context of Growth Cones

• We investigated the binding of GAP-43 to the growth-cone membrane by mutational analysis and by laser-scanning confocal microscopy of fusion proteins that included regions of GAP-43 and chloramphenicol acetyltransferase (CAT) [35].
• The three-dimensional reconstructions show that the cytoplasmic components of growth cones, including the membrane-bound sacs and multilamellar stacks revealed by freeze substitution, are polarized along the axis of these growth cones, which suggests that they have a role in recycling of membrane during elongation of the growth cone [36].
• Using confocal and electron microscopies, we have also found that atlastin-1 is highly enriched in vesicular structures within axonal growth cones and varicosities as well as at axonal branch points in cultured cerebral cortical neurons, prefiguring a functional role for atlastin-1 in axonal development [37].
• Single cell cultures show an enrichment of NrCAM in the distal axon and growth cone [38].
• Three additional lines of evidence support this possibility: TOAD-64 is upregulated following neuronal induction of P19 and PC12 cells; the protein is found in lamellipodia and filopodia of growth cones; and axotomy of the sciatic nerve induces reexpression [39].

References