Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons

Bomze, Howard M.; Bulsara, Ketan R.; Iskandar, Bermans J.; Caroni, Pico; Skene, J. H. Pate

doi:10.1038/82881

Cited by 337 publications

(243 citation statements)

References 51 publications

(85 reference statements)

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“…This occurs when COS-7 cells, which do not express GAP-43, are transfected with a constitutively active form of cdc42 [34]. Consistent with this idea, the effects of GAP-43 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and constitutively active cdc42 together are additive [34]. Since the first 14 residues of GAP-43 do not contain the protein kinase C phosphorylation site, it was suggested that interaction of only the first 14 residues with membranes is sufficient to Fig.…”

Section: Gap-43 G Proteins Small Gtpases and Filopodiasupporting

confidence: 57%

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Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Denny

2006

203

166

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GAP-43 is an intracellular growth-associated protein that appears to assist neuronal pathfinding and branching during development and regeneration, and may contribute to presynaptic membrane changes in the adult, leading to the phenomena of neurotransmitter release, endocytosis and synaptic vesicle recycling, long-term potentiation, spatial memory formation, and learning. GAP-43 becomes bound via palmitoylation and the presence of three basic residues to membranes of the early secretory pathway. It is then sorted onto vesicles at the late secretory pathway for fast axonal transport to the growth cone or presynaptic plasma membrane. The palmitate chains do not serve as permanent membrane anchors for GAP-43, because at steady-state most of the GAP-43 in a cell is membrane-bound but is not palmitoylated. Filopodial extension and branching take place when GAP-43 is phosphorylated at Ser-41 by protein kinase C, and this occurs following neurotrophin binding and the activation of numerous small GTPases. GAP-43 has been proposed to cluster the acidic phospholipid phosphatidylinositol 4,5-bisphosphate in plasma membrane rafts. Following GAP-43 phosphorylation, this phospholipid is released to promote local actin filament-membrane attachment. The phosphorylation also releases GAP-43 from calmodulin. The released GAP-43 may then act as a lateral stabilizer of actin filaments. N-terminal fragments of GAP-43, containing 10-20 amino acids, will activate heterotrimeric G proteins, direct GAP-43 to the membrane and lipid rafts, and cause the formation of filopodia, possibly by causing a change in membrane tension. This review will focus on new information regarding GAP-43, including its binding to membranes and its incorporation into lipid rafts, its mechanism of action, and how it affects and is affected by extracellular agents.

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Section: Gap-43 G Proteins Small Gtpases and Filopodiasupporting

confidence: 57%

“…This suggests that signals must be transduced from particular extracellular molecules to GAP-43 in order for neurite outgrowth to occur. Overexpression of GAP-43 and CAP-23 in dorsal root ganglion neurons increased axon growth in vitro and in the injured spinal cord [10].…”

Section: Gap-43 Neurotrophins Cell Adhesion Molecules Developmentmentioning

confidence: 99%

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Denny

2006

203

166

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“…Similarly, growth-associated protein 43 (Gap43), which has long been associated with regenerating axons, can also promote neurite outgrowth, but not through an inhibitory environment 98,99 . In transgenic mice that overexpress Gap43, together with a similar protein Cap23, lesioned dorsal column axons will spontaneously regenerate into a peripheral nerve graft in the absence of a peripheral conditioning lesion 100 . However, the ability of…”

Section: Future Perspectivesmentioning

confidence: 99%

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

2003

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“…But which genes are sufficient, and which are necessary? Using a candidate gene approach, Skene and colleagues recently showed that overexpressing two growth cone proteins, GAP-43 and CAP-23, is sufficient to dramatically increase DRG axon growth in vitro and in the injured spinal cord in vivo (Bomze et al 2001). Experiments are underway to characterize the differences in axon growth between developing and regenerating sensory neurons.…”

Section: Do Pns Neurons Lose Their Intrinsic Axon Growth Ability?mentioning

confidence: 99%

How does an axon grow?

Goldberg¹

2003

Genes Dev.

204

138

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How do axons grow during development, and why do they fail to regrow when injured? In the complicated mesh of our nervous system, the axon is the information superhighway, carrying all of the data we use to sense our environment and carry out behaviors. To wire up our nervous system properly, neurons must elongate their axons during development to reach their targets. This is no simple task, however. The complex morphology of axons and dendrites puts neurons among the most intricate and beautiful cells in the body. Knowledge of how neurons extend axons and dendrites, elongate at a particular rate, and stop growing at the proper time is critical to understanding the development of our nervous system, yet the regulation of these processes is poorly understood. Considerable attention in recent years has focused on understanding how growth cones are guided and steered through complicated pathways (for review, see Schmidt and Hall 1998;Mueller 1999), and even how neurons initiate new processes (for review, see Da Silva and Dotti 2002), but what mechanisms are involved in elongation itself? Are environmental signals needed to drive axon growth and, if so, what are the intracellular molecular mechanisms by which they induce elongation? What controls the rate of axon growth? How do CNS neurons know whether to extend axons or dendrites? Is the signaling of axon versus dendrite growth attributable to different extracellular signals, different neuronal states, or both? All of these questions bear critically on our understanding of axon growth and here I review recent answers and approaches to the above questions, and highlight their relevance during development, injury, and disease.

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Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons

Cited by 337 publications

References 51 publications

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

How does an axon grow?

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