Rapid arrest of axon elongation by brefeldin A: A role for the small GTP-binding protein ARF in neuronal growth cones

Hess, Douglas T.; Smith, Deanna S.; Patterson, Sean I.; Kahn, Richard; Skene, J. H. Pate; Norden, Jeanette J.

doi:10.1002/(sici)1097-4695(199901)38:1<105::aid-neu8>3.0.co;2-m

Cited by 15 publications

(10 citation statements)

References 80 publications

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“…However, previous work is inconsistent with ARNO's function in axonal growth being mediated by ARF1. Incubation of neurons with brefeldin A, a drug that is known to inhibit ARF1 GEFs, inhibits axonal extension (Jareb and Banker, 1997;Hess et al, 1999), in contrast with our finding that ARNO inhibition increases axonal extension.…”

Section: Effects Of Arno Upon Axonogenesis Are Mediated By Downstreamsupporting

confidence: 54%

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ARNO and ARF6 Regulate Axonal Elongation and Branching through Downstream Activation of Phosphatidylinositol 4-Phosphate 5-Kinase α

Hernández-Deviez

Roth

Casanova

et al. 2004

MBoC

154

121

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In the developing nervous system, controlled neurite extension and branching are critical for the establishment of connections between neurons and their targets. Although much is known about the regulation of axonal development, many of the molecular events that regulate axonal extension remain unknown. ADP-ribosylation factor nucleotidebinding site opener (ARNO) and ADP-ribosylation factor (ARF)6 have important roles in the regulation of the cytoskeleton as well as membrane trafficking. To investigate the role of these molecules in axonogenesis, we expressed ARNO and ARF6 in cultured rat hippocampal neurons. Expression of catalytically inactive ARNO or dominant negative ARF6 resulted in enhanced axonal extension and branching and this effect was abrogated by coexpression of constitutively active ARF6. We sought to identify the downstream effectors of ARF6 during neurite extension by coexpressing phosphatidyl-inositol-4-phosphate 5-Kinase ␣ [PI(4)P 5-Kinase ␣] with catalytically inactive ARNO and dominant negative ARF6. We found that PI(4)P 5-Kinase ␣ plays a role in neurite extension and branching downstream of ARF6. Also, expression of inactive ARNO/ARF6 depleted the actin binding protein mammalian ena (Mena) from the growth cone leading edge, indicating that these effects on axonogenesis may be mediated by changes in cytoskeletal dynamics. These results suggest that ARNO and ARF6, through PI(4)P 5-Kinase ␣, regulate axonal elongation and branching during neuronal development.

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Section: Effects Of Arno Upon Axonogenesis Are Mediated By Downstreamsupporting

confidence: 54%

“…In neurons, ARF proteins may regulate axonal elongation because treatment with brefeldin A inhibited axonal growth (Jareb and Banker, 1997;Hess et al, 1999). ARNO is a brefeldin A-insensitive GEF that catalyzes exchange on ARF1 and ARF6 (Chardin et al, 1996;Frank et al, 1998a).…”

Section: Introductionmentioning

confidence: 99%

ARNO and ARF6 Regulate Axonal Elongation and Branching through Downstream Activation of Phosphatidylinositol 4-Phosphate 5-Kinase α

Hernández-Deviez

Roth

Casanova

et al. 2004

MBoC

154

121

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“…5), these data suggest that a functional equivalent of the rough ER and Golgi complex may indeed exist in the axonal compartment. Hess et al (1999) provided evidence that functional Golgi contributes to axon growth, because inhibition of ADPribosylation factor, a protein involved in ER-Golgi and intra-Golgi transport, caused rapid retraction of growth cones.…”

Section: Er Proteins Are Synthesized In Drg Axonsmentioning

confidence: 99%

Differential Transport and Local Translation of Cytoskeletal, Injury-Response, and Neurodegeneration Protein mRNAs in Axons

Willis¹,

Li²,

Zheng³

et al. 2005

J. Neurosci.

360

391

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Recent studies have begun to focus on the signals that regulate axonal protein synthesis and the functional significance of localized protein synthesis. However, identification of proteins that are synthesized in mammalian axons has been mainly based on predictions. Here, we used axons purified from cultures of injury-conditioned adult dorsal root ganglion (DRG) neurons and proteomics methodology to identify axonally synthesized proteins. Reverse transcription (RT)-PCR from axonal preparations was used to confirm that the mRNA for each identified protein extended into the DRG axons. Proteins and the encoding mRNAs for the cytoskeletal proteins ␤-actin, peripherin, vimentin, ␥-tropomyosin 3, and cofilin 1 were present in the axonal preparations. In addition to the cytoskeletal elements, several heat shock proteins (HSP27, HSP60, HSP70, grp75, ␣B crystallin), resident endoplasmic reticulum (ER) proteins (calreticulin, grp78/BiP, ERp29), proteins associated with neurodegenerative diseases (ubiquitin C-terminal hydrolase L1, rat ortholog of human DJ-1/Park7, ␥-synuclein, superoxide dismutase 1), anti-oxidant proteins (peroxiredoxins 1 and 6), and metabolic proteins (e.g., phosphoglycerate kinase 1 (PGK 1), ␣ enolase, aldolase C/Zebrin II) were included among the axonally synthesized proteins. Detection of the mRNAs encoding each of the axonally synthesized proteins identified by mass spectrometry in the axonal compartment indicates that the DRG axons have the potential to synthesize a complex population of proteins. Local treatment of the DRG axons with NGF or BDNF increased levels of cytoskeletal mRNAs into the axonal compartment by twofold to fivefold but had no effect on levels of the other axonal mRNAs studied. Neurotrophins selectively increased transport of ␤-actin, peripherin, and vimentin mRNAs from the cell body into the axons rather than changing transcription or mRNA survival in the axonal compartment.

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“…Moreover, Hess et al (40) provided evidence that functional Golgi contributes to axon growth, because inhibition of ADPribosylation factor, a protein involved in ER to Golgi and intraGolgi transport, caused rapid retraction of growth cones. Based on its sequence homology, LRRK2 has been associated with the family of Rab-GTPases that are involved in ER to Golgi trafficking and the docking of ER-derived transport vesicles at the Golgi membrane (41).…”

Section: Tablementioning

confidence: 99%

Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth

Sämann

Hegermann

Gromoff

et al. 2009

Journal of Biological Chemistry

175

168

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Mutations in two genes encoding the putative kinases LRRK2 and PINK1 have been associated with inherited variants of Parkinson disease. The physiological role of both proteins is not known at present, but studies in model organisms have linked their mutants to distinct aspects of mitochondrial dysfunction, increased vulnerability to oxidative and endoplasmic reticulum stress, and intracellular protein sorting. Here, we show that a mutation in the Caenorhabditits elegans homologue of the PTEN-induced kinase pink-1 gene resulted in reduced mitochondrial cristae length and increased paraquat sensitivity of the nematode. Moreover, the mutants also displayed defects in axonal outgrowth of a pair of canal-associated neurons. We demonstrate that in the absence of lrk-1, the C. elegans homologue of human LRRK2, all phenotypic aspects of pink-1 loss-offunction mutants were suppressed. Conversely, the hypersensitivity of lrk-1 mutant animals to the endoplasmic reticulum stressor tunicamycin was reduced in a pink-1 mutant background. These results provide the first evidence of an antagonistic role of PINK-1 and LRK-1. Due to the similarity of the C. elegans proteins to human LRRK2 and PINK1, we suggest a common role of both factors in cellular functions including stress response and regulation of neurite outgrowth. This study might help to link pink-1/PINK1 and lrk-1/LRRK2 function to the pathological processes resulting from Parkinson disease-related mutants in both genes, the first manifestations of which are cytoskeletal defects in affected neurons. Mutations in the Parkinson disease (PD)2 -related gene PINK1 have been associated with increased sensitivity to oxidative stress and mitochondrial dysfunction (1-4). Although a series of reports support a localization of PINK1 only in mitochondria (5-7), recent studies have shown that a portion of endogenous PINK1 is also distributed to the cytoplasm (8 -11). Notably, the cytoplasmic kinase activity and not the mitochondrial targeting of PINK1 seems to be prerequisite of its protective effects against mitochondrial stress (12).The GTPase-regulated kinase LRRK2, another gene associated with familial PD, has been linked to the biogenesis and regulation of vesicular transport (13,14). In support of this notion, the C. elegans lrk-1, the LRRK2 homologue, has recently been shown to be involved in synaptobrevin-associated vesicular transport (15). Moreover, the Dictyostelium homologue of LRRK2/LRK-1 proteins, GbpC, a cGMP-binding protein is required for the normal phosphorylation and cytoskeletal assembly of myosin (16). Based on this data, it had been anticipated that PINK1/PINK-1 and LRRK2/LRK-1 might be involved in distinct cellular functions, whereas pathological mutations in both genes, leading either to loss-of-function (PINK1) or gain-of-function (LRRK2), result in a similar phenotype, the loss of dopaminergic neurons.In the present study, we found a functional connection between their Caenorhabditits elegans homologues pink-1 and lrk-1. We demonstrate that loss of C. elega...

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Rapid arrest of axon elongation by brefeldin A: A role for the small GTP-binding protein ARF in neuronal growth cones

Cited by 15 publications

References 80 publications

ARNO and ARF6 Regulate Axonal Elongation and Branching through Downstream Activation of Phosphatidylinositol 4-Phosphate 5-Kinase α

ARNO and ARF6 Regulate Axonal Elongation and Branching through Downstream Activation of Phosphatidylinositol 4-Phosphate 5-Kinase α

Differential Transport and Local Translation of Cytoskeletal, Injury-Response, and Neurodegeneration Protein mRNAs in Axons

Caenorhabditits elegans LRK-1 and PINK-1 Act Antagonistically in Stress Response and Neurite Outgrowth

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