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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pattern of axonal projections early in the development of the nervous system lacks the precision present in the adult. During a developmental process of refinement, mistargeted projections are eliminated while correct projections are retained. Previous studies suggest that during development nitric oxide (NO) is involved in the elimination of mistargeted retinal axons, whereas brain-derived neurotrophic factor (BDNF) may stabilize retinal axon arbors. It is unclear whether these neuromodulators interact. This study showed that NO induced growth cone collapse and retraction of developing retinal axons. This effect was not attributable to NO-induced neurotoxicity. BDNF protected growth cones and axons from the effects of NO. This effect was specific to BDNF, because neither nerve growth factor (NGF) nor neurotrophin-3 (NT-3) prevented NO-induced growth cone collapse and axon retraction. Exposure to both BDNF and NO, but not either factor alone, stabilized growth cones and axons. Stabilized axons exhibited minimal retraction or extension. This response appears to be a new axon "state" and not simply a partial amelioration of the effect of NO, because lower doses of BDNF or NO allowed axon extension. Furthermore, BDNF/NO-induced growth cone stabilization correlated with the appearance of a cytochalasin D-resistant population of actin filaments. BDNF protection from NO likely was mediated locally at the level of the growth cone, because growth cones or individual filopodia in contact with BDNF-coated beads were protected from NO-induced collapse. These findings suggest a cellular mechanism by which some axonal connections are stabilized and some are eliminated during development.
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PMID:Stabilization of growing retinal axons by the combined signaling of nitric oxide and brain-derived neurotrophic factor. 1066 36

We studied temporal changes in mRNA expression patterns for nitric oxide synthase (NOS), cytokines, neurotrophins and neurotrophin receptors in the dorsal root ganglion (DRG) of the rat, after application of a tourniquet to the hind limb. Collapsed myelin and degenerated axons were observed in the tourniquet segment of the sciatic nerve. Gene expression level of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) was significantly increased in ipsilateral DRG samples at 4h after application of the tourniquet but not in the contralateral or control DRG samples. Upregulation of tumor necrosis factor (TNF)-alpha, activating transcription factor (ATF)-3 and neurotrophin-3 (NT3) expressions began at 1h after application of the tourniquet in ipsilateral DRGs. It is likely that transient expression of these molecules triggers secondary events that may be beneficial to wound repair and regeneration.
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PMID:Expression of cytokines, neurotrophins, neurotrophin receptors and NOS mRNA in dorsal root ganglion of a rat tourniquet model. 1293 8

Neurotrophins have been known to play a pivotal role in axonal guidance. Recent research has implicated the role of extracelluar matrix molecules in co-ordinating axonal movement. In this study, we examined the influence of neurotrophins (nerve growth factor (NGF) and neurotrophin-3 (NT-3)) and extracellular matrix molecules (laminin, fibronectin, and poly-l-lysin) on sensory neurite outgrowth in thoracic dorsal root ganglia (DRG) dissected from rats at embryonic day 13. Adjacent DRG were embedded in a collagen gel matrix and supplemented with NGF or NT-3. Under NT-3 conditions, DRG axons extended towards each other and intermingled, while neurites from NGF-treated DRG demonstrated a strong repellent effect, resulting in turning responses and growth cone collapse. This effect was not observed on a collagen culture surface. Interestingly, the composition of the extracellular matrix strongly influenced the observed repellent effect. Sensory neurites from NGF-stimulated DRG again demonstrated a repellent effect when plated on a laminin surface, but showed intermingling behavior when plated on poly-l-lysin or fibronectin. This observation suggests that a factor secreted by NGF-treated DRG axons interacts with laminin, enabling repulsion. This factor and its interaction with the extracellular matrix play an important role in the mechanism of sensory axonal pathfinding.
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PMID:Neurotrophins and extracellular matrix molecules modulate sensory axon outgrowth. 1503 86

Aggrecan is one of the major chondroitin sulfate proteoglycans (CSPGs) expressed in the central nervous system. The signaling pathways activated downstream of cell interaction with aggrecan and with CSPGs in general and the importance of chondroitin sulfate-glycosaminoglycan side chains in their inhibition are unclear. Therefore, to analyze the effect of different components of aggrecan in inhibiting neurite growth, neurite outgrowth was quantified in an in vitro model in which chick dorsal root ganglion (DRG) explants were grown on substrates containing aggrecan bound to hyaluronan and link protein as a macromolecular aggregate, aggrecan monomers, hyaluronan, or ChABC-treated aggrecan. Aggrecan aggregate, aggrecan monomer, and hyaluronan inhibited neurite outgrowth from nerve growth factor (NGF)- and neurotrophin-3 (NT3)-responsive DRG neurons. Aggrecan inhibition was dependent on its chondroitin sulfate-glycosaminoglycans, as ChABC digestion alleviated neurite inhibition because of aggrecan. Growth cones displayed full or partial collapse on aggrecan aggregate, hyaluronan, and ChABC-treated aggrecan. Inhibition of Rho kinase (ROCK) with Y27632 increased neurite growth on some but not all of the aggrecan components tested. With NGF in the culture medium, Y27632 increased neurite outgrowth on aggrecan aggregate, monomers, and ChABC-treated aggrecan, but not on hyaluronan. The ROCK inhibitor also increased NT3-responsive outgrowth on aggrecan aggregate and hyaluronan, but not on ChABC-treated aggrecan. This study showed that the matrix proteoglycan aggrecan and its components have multiple effects on neurite outgrowth and that some of these effects involve the Rho/ROCK pathway.
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PMID:Aggrecan components differentially modulate nerve growth factor-responsive and neurotrophin-3-responsive dorsal root ganglion neurite growth. 1791 43

Recent evidence suggests that growth cone responses to guidance cues require local protein synthesis. Using chick neurons, we investigated whether protein synthesis is required for growth cones of several types to respond to guidance cues. First, we found that global inhibition of protein synthesis stops axonal elongation after 2 h. When protein synthesis inhibitors were added 15 min before adding guidance cues, we found no changes in the typical responses of retinal, sensory, and sympathetic growth cones. In the presence of cycloheximide or anisomycin, ephrin-A2, slit-3, and semaphorin3A still induced growth cone collapse and loss of actin filaments, nerve growth factor (NGF) and neurotrophin-3 still induced growth cone protrusion and increased filamentous actin, and sensory growth cones turned toward an NGF source. In compartmented chambers that separated perikarya from axons, axons grew for 24-48 h in the presence of cycloheximide and responded to negative and positive cues. Our results indicate that protein synthesis is not strictly required in the mechanisms for growth cone responses to many guidance cues. Differences between our results and other studies may exist because of different cellular metabolic levels in in vitro conditions and a difference in when axonal functions become dependent on local protein synthesis.
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PMID:Protein synthesis in distal axons is not required for growth cone responses to guidance cues. 1915 91