GAP‐43 mRNA in growth cones is associated with HuD and ribosomes

Smith, Catherine L.; Afroz, Rownak; Bassell, Gary J.; Furneaux, Henry; Perrone‐Bizzozero, Nora I.; Burry, Richard W.

doi:10.1002/neu.20038

Cited by 80 publications

(67 citation statements)

References 75 publications

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“…PKC␣ colocalization with nELAV proteins after stimulation and the increase in their threonine phosphorylation are also in agreement with a direct kinase activity of PKC␣ on HuB, HuC, and HuD proteins, which could take place at the five conserved putative threonine PKC phosphorylation sites that they share in the primary amino acid sequence. Given the very short time frame of nELAV and GAP-43 protein up-regulation induced by PKC stimulation (15 min), it is tempting to speculate that this PKC-induced control of gene expression is exerted at the translational level, which would be in agreement with the polysomal localization of nELAV proteins in the neuronal cytoplasm (30,31,49,51) and with their proposed activity of translational enhancement (49,52,53). The up-regulation of the nELAV proteins themselves could be an autoregulation mechanism: We already know that the Drosophila ELAV protein is autoregulated at the mRNA level (54) and that murine HuB mRNA is bound by the HuB protein itself (55).…”

Section: Discussionmentioning

confidence: 83%

Neuronal ELAV proteins enhance mRNA stability by a PKCα-dependent pathway

Pascale

Amadio

Scapagnini

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

121

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Long-lasting changes in cellular functions require reprogramming of protein synthesis as a result of cell signaling events that influence nuclear transcription and͞or the fate of the transcribed mRNAs, ultimately leading to changed mRNA availability to the ribosome. Posttranscriptional mechanisms are emerging as key controllers of gene expression (reviewed in refs. 1 and 2) and are postulated to be critical for the localized changes in protein levels involved in cell differentiation and in the maintenance of the differentiated phenotype, especially in polarized cells such as neurons (3). Modulation of mRNA decay appears to be an efficient posttranscriptional way of controlling expression, because small changes in mRNA half-life can radically alter the abundance of a given mRNA and the amount of the relevant protein (4). Indeed, the decay rates of many mRNAs are governed by defined sequence determinants and by RNA-binding proteins (RBPs) acting on these determinants. The best-characterized regulative cis motifs in mammalian mRNAs are the AREs (adenine-and uridine-rich elements), which are found in the 3Ј UTRs of mRNAs endowed with a rapid response to cell environmental stimuli, as in many cytokines and oncogenes (reviewed in ref. 5).In the human genome, a general ARE consensus is present in 5-8% of expressed genes (6), and it represents a docking site for RBPs controlling mRNA stability, probably by modulation of exosome activity (7). ARE-dependent mRNA decay has been shown to be a target of at least two signaling cascades. The first is the p38 mitogen-activated protein kinase (MAPK)-MAPKAPK2 pathway, which, when activated, stabilizes ARE-bearing interleukin mRNAs (8-10), possibly through inactivation of the ARE-binding, mRNA-destabilizing RBP tristetraprolin (11, 12). The second pathway, which has been less investigated, is triggered by phorbol esters (phorbol 12-myristate 13-acetate, PMA) and calcium ionophore administration to culture cells, leading again to stabilization of ARE-bearing mRNAs (13-19). For its features, this pathway could involve the calcium-and diacylglycerol-regulated PKC isozymes, possibly resulting in the activation of a downstream function able to induce stabilization of ARE-bearing mRNAs. Fifteen years ago, Malter and coworkers (20, 21) identified a factor of Ϸ32 kDa, which they called AUBF for AU-rich binding factor, that was induced to bind ARE sequences after brief PMA treatment or calcium influx and was inactivated by dephosphorylation in peripheral blood mononuclear cells. AUBF was shown to be almost entirely located on polysomes when stimulated (22).ELAV (embryonic lethal abnormal vision) proteins, or Hu antigens, represent the best-studied ARE-binding RBPs and are known from a substantial body of evidence to stabilize target mRNAs in the cytoplasm (reviewed in refs. 23 and 24). In vertebrates, HuB, HuC, and HuD are neuron-specific members of the ELAV family (nELAV proteins), whereas HuR is ubiquitously expressed; all four proteins are highly homologous in sequence, are Ϸ40 kDa in s...

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Section: Discussionmentioning

confidence: 83%

Neuronal ELAV proteins enhance mRNA stability by a PKCα-dependent pathway

Pascale

Amadio

Scapagnini

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

121

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“…GAP-43 protein and mRNA appear to be axonally transported, suggesting that somatic induction may be followed by distal distribution. This protein may also be synthesized within the growth cone, perhaps explaining the enhanced striatal GAP-43 protein levels detected here (Meiri et al, 1991,Perrone-Bizzozero and Bolognani, 2002,Smith et al, 2004. Although most striatal GAP-43 originates extrinsically, intrinsic sources of GAP-43 may also contribute to this change (DiFiglia et al, 1990,Iwata et al, 1999.…”

Section: Discussionmentioning

confidence: 83%

Intrastriatal dopamine D1 antagonism dampens neural plasticity in response to motor cortex lesion

2007

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Motor cortex lesions in rats partially denervate the striatum, producing behavioral deficits and inducing reactive neuroplasticity. Plastic responses include changes in growth-associated protein marker expression and anatomical restructuring. Corticostriatal plasticity is dependent on dopamine at the striatal target, where D1 receptor signaling reinforces behaviorally relevant neural activity. To determine whether striatal dopamine D1 receptor signaling is important for the growth-associated protein responses and behavioral recovery that follow unilateral motor cortex aspiration, the dopamine D1 receptor antagonist SCH23390 was intrastriatally infused in cortically lesioned animals. After a cortical aspiration lesion in Long Evans rats, the growth-associated proteins SCG10 and GAP-43 were upregulated in the cortex contralateral to the lesion at 30 days post-lesion. However, continuous unilateral intrastriatal infusion of SCH23390 prevented this aspiration-induced upregulation. Furthermore, lesioned rats demonstrated spontaneous sensorimotor improvement, in terms of limb-use symmetry, about one month post-lesion. This improvement was prevented with chronic intrastriatal SCH23390 infusion. The D1 receptor influence may be important to normalize corticostriatal activity (and observable behavior), either in a long-term manner or temporarily until other more permanent means of synaptic regulation, such as sprouting or synaptogenesis, may be implemented. Keywords cortical ablation; striatum; SCH23390The ability to reorganize neural connections according to changing environmental cues is essential to the formation of the wide network of limbic, striatal, and cortical circuits that regulate the complex array of human behaviors. Generally referred to as neural plasticity, these adaptive processes are most obvious in the developing brain, but are also utilized throughout adulthood as new skills and memories are acquired. Likewise, when the brain is damaged by trauma or disease, adaptive mechanisms of plasticity are brought into play and are critical for determining the limits of functional recovery (Ivanco and Greenough, 2000,Johansson, 2000,Nudo et al., 2001,Gonzalez and Kolb, 2003. These adaptive processes are governed by local extra-and intracellular signals and can be manipulated by various experimental interventions including: exercise (Cotman and Berchtold, 2002,Gomez-Pinilla et al., 2002) Tel: 323-442-2126; Fax: 323-442-2127. E-mail address: elizabjd@usc.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (van Praag et al., 2000), motor skills training (Plautz et a...

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“…Ribosomes and mRNA have been localized in mammalian axons and growth cones [14]. Although ribosomes, HuD, and GAP-43 mRNA have been detected in axonal growth cones [86], this may be a secondary site of synthesis, as axonal protein synthesis does not appear to be necessary if protein synthesis in the cell body is available [105]. It is nevertheless possible that local protein synthesis is necessary to provide growth-related proteins that sensitize the growth cone to guidance cues [35].…”

Section: Synthesis Of Gap-43mentioning

confidence: 99%

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

Denny

2006

197

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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GAP‐43 mRNA in growth cones is associated with HuD and ribosomes

Cited by 80 publications

References 75 publications

Neuronal ELAV proteins enhance mRNA stability by a PKCα-dependent pathway

Neuronal ELAV proteins enhance mRNA stability by a PKCα-dependent pathway

Intrastriatal dopamine D1 antagonism dampens neural plasticity in response to motor cortex lesion

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

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