The Neuronal Growth-Associated Protein GAP-43 Induces Filopodia in Non-Neuronal Cells

Zuber, Mauricio X.; Goodman, Daniel; Karns, Larry R.; Fishman, Mark C.

doi:10.1126/science.2658062

Cited by 206 publications

(93 citation statements)

References 28 publications

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“…Rather, they were similar to the filopodia-like processes budding from B-50/GAP-43-overexpressing non-neuronal cells (Zuber et al, 1989;Yankner et al, 1990;Widmer and Caroni, 1993;Verhaagen et al, 1994). This observation indicates that B-50/GAP-43-induced Purkinje cell sprouts are unable to establish new synaptic connections.…”

Section: B-50/gap-43 Overexpression Does Not Modify the Intact Purkinmentioning

confidence: 82%

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

et al. 1997

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B-50/GAP-43 is a nervous tissue-specific protein, the expression of which is associated with axon growth and regeneration. Its overexpression in transgenic mice produces spontaneous axonal sprouting and enhances induced remodeling in several neuron populations (Aigner et al., 1995;Holtmaat et al., 1995). We examined the capacity of this protein to increase the regenerative potential of injured adult central axons, by inducing targeted B-50/GAP-43 overexpression in Purkinje cells, which normally show poor regenerative capabilities. Thus, transgenic mice were produced in which B-50/GAP-43 overexpression was driven by the Purkinje cell-specific L7 promoter. Uninjured transgenic Purkinje cells displayed normal morphology, indicating that transgene expression does not modify the normal phenotype of these neurons. By contrast, after axotomy numerous transgenic Purkinje cells exhibited profuse sprouting along the axon and at its severed end. Nevertheless, despite these growth phenomena, which never occurred in wild-type mice, the severed transgenic axons were not able to regenerate, either spontaneously or into embryonic neural or Schwann cell grafts placed into the lesion site. Finally, although only a moderate Purkinje cell loss occurred in wild-type cerebella after axotomy, a considerable number of injured transgenic neurons degenerated, but they could be partially rescued by the different transplants placed into the lesion site. Thus, B-50/GAP-43 overexpression substantially modifies Purkinje cell response to axotomy, by inducing growth processes and decreasing their resistance to injury. However, the presence of this protein is not sufficient to enable these neurons to accomplish a full program of axon regeneration.

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Section: B-50/gap-43 Overexpression Does Not Modify the Intact Purkinmentioning

confidence: 82%

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

et al. 1997

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“…GAP-43 transfected into non-neuronal cells is known to induce filopodia (Zuber et al, 1989). We showed that the repetitive stimulation is favorable for filopodial sprouting.…”

Section: Dependence On Ca2+mentioning

confidence: 87%

Rapid sprouting of filopodia in nerve terminals of chromaffin cells, PC12 cells, and dorsal root neurons induced by electrical stimulation

Manivannan

Terakawa

1994

J. Neurosci.

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Rapid morphological changes induced by direct electrical stimulation of nerve terminals were studied by using video-enhanced differential interference contrast microscopy at a very high magnification (12,000x). We used mainly cultured bovine chromaffin cells, which developed neurite-like processes, and PC12 cells, which showed neuronal differentiation upon NGF treatment. In a few cases, primary neurons of the rat dorsal root ganglion were also examined. Brief pulse stimulation of the terminals and varicosities induced exocytosis accompanied by rapid formation of filopodia. These filopodia, 0.1–0.2 micron in diameter and up to 10 microns in length, formed within a few hundreds of milliseconds and then retracted within tens of seconds. They could also be induced by K depolarization. This rapid filopodial sprouting strongly depended on the presence of extracellular Ca2+ and could be abolished in a medium containing a Ca chelator (EGTA) or La2+. Anti-cytoskeletal agents colchicine and cytochalasin B failed to block this response completely but lidocaine fully suppressed it. Quantitative analysis of exocytosis and filopodial sprouting showed that they were independent events, not directly linked to each other, having different thresholds usually higher for filopodial formation. In PC12 cells, the extent of filopodial sprouting varied with the state of differentiation of the cells, suggesting a functional role of rapid sprouting during a particular phase of their differentiation. Filopodia could be induced with greater ease by repetitive stimulation. The same responses may occur at growth cones approaching the target cells or even at mature synapses particularly after repetitive electrical activity, possibly playing a role in use-dependent synapse formation or plasticity.

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“…Studies on the neuronal proteins GAP-43 and paralemmin show that palmitoylation is important for localizing these proteins to filopodia (Zuber et al, 1989a(Zuber et al, , 1989bKutzleb et al, 1998). In contrast, dual palmitoylation of PSD-95 is necessary for appropriate postsynaptic localization to dendritic spines (Craven et al, 1999;El-Husseini et al, 2000;El-Husseini and Bredt, 2002).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein Motifs

Gauthier-Campbell

Bredt

Murphy

et al. 2004

MBoC

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Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes. INTRODUCTIONNeurons possess an elaborate plasma membrane architecture that includes axons, dendrites, and synaptic sites (Da Silva and Dotti, 2002). Modulation of the plasma membrane shape and composition regulate processes outgrowth, axonal development, dendritic branching, and the construction of synapses (Jontes and Smith, 2000). These changes are regulated by interactions between the constituents of the plasma membrane, the exo/endocytic vesicles, and the cytoskeleton (Wood and Martin, 2002). In nonneuronal cells, differential modulation of membrane flow can result in the formation of processes such as microspikes, lamellopodia, and filopodia (Wood and Martin, 2002). However, factors that regulate the formation and maintenance of specific classes of membranous processes in neuronal cells remain poorly understood.Dendritic filopodia, cell surface extensions filled with tight parallel bundles of actin filaments, are thought to be precursors for developing synapses (Dailey and Smith, 1996;Small, 1988). Filopodia are typically 5-35 m in length and rapidly alter their position and shape. In developing axons, filopodia occur at the tips of growth cones and may aid the axon in finding its appropriate target. In dendrites, filopodia act as precursors to spines, short bulbous protrusions of the dendrite that form excitatory postsynaptic contacts on many neurons (Jontes and Smith, 2000). Thus, changes in membrane structure that result in the formation of filopodia are likely important in axonal guidance and spine formation. In contrast, dendritic branching is thought to be mediated via an actin and/or microtubule-dependent mechanisms (Jan and Jan, 2003). Recent studies showed that in early neuronal development dendrites originate from lamellopodia and short neurites (Jan and Jan, ...

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The Neuronal Growth-Associated Protein GAP-43 Induces Filopodia in Non-Neuronal Cells

Cited by 206 publications

References 28 publications

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

Targeted Overexpression of the Neurite Growth-Associated Protein B-50/GAP-43 in Cerebellar Purkinje Cells Induces Sprouting after Axotomy But Not Axon Regeneration into Growth-Permissive Transplants

Rapid sprouting of filopodia in nerve terminals of chromaffin cells, PC12 cells, and dorsal root neurons induced by electrical stimulation

Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein Motifs

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