The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo

Wood, Jonathan; Landers, Jennifer A.; Bingley, Megan; McDermott, Christopher J.; Thomas-McArthur, Vickie; Gleadall, Lisa J.; Shaw, Pamela J.; Cunliffe, Vincent T.

doi:10.1093/hmg/ddl212

Cited by 134 publications

(126 citation statements)

References 46 publications

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“…We therefore conclude that reduced levels of katna1 expression caused spinal motor axon outgrowth defects in vivo. We also demonstrated that the effects of the spg4atg1 and spg4e7i7 morpholinos (Wood et al, 2006) on spinal motor axon outgrowth were independent of p53 ( Fig. 1E, Fig.…”

Section: Dmmbiologistsorg 744mentioning

confidence: 53%

“…We previously demonstrated a crucial requirement for spastin to promote axon outgrowth in the zebrafish embryo (Wood et al, 2006). Interestingly, the closely related microtubule-severing protein P60-katanin has also been shown to promote axonal growth in cultured primary neurons (Ahmad et al, 1999;Karabay et al, 2004).…”

Section: Like Spastin P60-katanin Is Required For Axon Outgrowth Inmentioning

confidence: 99%

“…To block katna1 function, morpholino antisense oligonucleotides (MOs) were designed against the initiating AUG of katna1 (katna1aug1, 5Ј-TCATCCTGTAA GT -TAAAGTGGTCAG-3Ј) and against the exon-4-intron-4 splice donor site of katna1 (katna1e4i4, 5Ј-CACAGATCTTCCTCAC -CTTGTCTTC-3Ј). The spast AUG-blocking MO (spg4atg1), spast splice-blocking MO (spg4e7i7) and spast control MO (spg4CoMO) are described elsewhere (Wood et al, 2006). A standard control MO (CoMO) that targets human -globin pre-mRNA and a morpholino that targets zebrafish p53 were also used.…”

Section: Microinjection Of Morpholinos and Dna Constructsmentioning

confidence: 99%

“…To investigate the developmental requirements for spastin, we previously used morpholino antisense methods to knockdown spast expression in the zebrafish embryo and demonstrated a crucial requirement for spastin to promote axon outgrowth during embryonic development (Wood et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia

Butler

Wood

Landers

et al. 2010

Disease Models &Amp; Mechanisms

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SUMMARY Mutations in the SPAST (SPG4) gene, which encodes the microtubule-severing protein spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). Following on from previous work in our laboratory showing that spastin is required for axon outgrowth, we report here that the related microtubule-severing protein katanin is also required for axon outgrowth in vivo. Using confocal time-lapse imaging, we have identified requirements for spastin and katanin in maintaining normal axonal microtubule dynamics and growth cone motility in vivo, supporting a model in which microtubule severing is required for concerted growth of neuronal microtubules. Simultaneous knockdown of spastin and katanin caused a more severe phenotype than did individual knockdown of either gene, suggesting that they have different but related functions in supporting axon outgrowth. In addition, the microtubule-destabilising drug nocodazole abolished microtubule dynamics and growth cone motility, and enhanced phenotypic severity in spast-knockdown zebrafish embryos. Thus, disruption of microtubule dynamics might underlie neuronal dysfunction in this model, and this system could be used to identify compounds that modulate microtubule dynamics, some of which might have therapeutic potential in HSP.

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Section: Dmmbiologistsorg 744mentioning

confidence: 53%

Section: Like Spastin P60-katanin Is Required For Axon Outgrowth Inmentioning

confidence: 99%

Section: Microinjection Of Morpholinos and Dna Constructsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia

Butler

Wood

Landers

et al. 2010

Disease Models &Amp; Mechanisms

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show abstract

“…Severing regulates the number and mobility of MTs and the distribution of their plus ends (Baas et al, 2006) and may functionally link MT-severing to certain aspects of membrane trafficking (Allison et al, 2013). Studies on Drosophila and zebrafish indicate that experimental reductions of spastin can be harmful to axonal development (Sherwood et al, 2004;Trotta et al, 2004;Wood et al, 2006), but developmental abnormalities have not been observed in homozygous spastin knock-out mice (Tarrade et al, 2006;Kasher et al, 2009) or human patients with one inactive spastin allele. In addition, genetic analyses of HSP-SPG4 patients have not revealed a correlation between spastin levels and the severity of neurodegenerative symptoms (Yip et al, 2003, Shoukier et al, 2009, and there are even rare HSP patients with mutations in the SPG4 gene that are not function-blocking .…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics

et al. 2014

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Mutations to the SPG4 gene encoding the microtubule-severing protein spastin are the most common cause of hereditary spastic paraplegia. Haploinsufficiency, the prevalent model for the disease, cannot readily explain many of its key aspects, such as its adult onset or its specificity for the corticospinal tracts. Treatment strategies based solely on haploinsufficiency are therefore likely to fail. Toward developing effective therapies, here we investigated potential gain-of-function effects of mutant spastins. The full-length human spastin isoform called M1 or a slightly shorter isoform called M87, both carrying the same pathogenic mutation C448Y, were expressed in three model systems: primary rat cortical neurons, fibroblasts, and transgenic Drosophila. Although both isoforms had ill effects on motor function in transgenic flies and decreased neurite outgrowth from primary cortical neurons, mutant M1 was notably more toxic than mutant M87. The observed phenotypes did not result from dominant-negative effects of mutated spastins. Studies in cultured cells revealed that microtubules can be heavily decorated by mutant M1 but not mutant M87. Microtubule-bound mutant M1 decreased microtubule dynamics, whereas unbound M1 or M87 mutant spastins increased microtubule dynamics. The alterations in microtubule dynamics observed in the presence of mutated spastins are not consistent with haploinsufficiency and are better explained by a gain-offunction mechanism. Our results fortify a model wherein toxicity of mutant spastin proteins, especially mutant M1, contributes to axonal degeneration in the corticospinal tracts. Furthermore, our results provide details on the mechanism of the toxicity that may chart a course toward more effective treatment regimens.

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Molecular Genetics of Hereditary Spastic Paraplegias

Stevanin

2010

Encyclopedia of Life Sciences

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Hereditary spastic paraplegias (HSPs), also known as Strümpell–Lorrain disease, are rare neurological conditions characterised by gradual spasticity and weakness of the lower limbs usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. The course is generally slowly progressive, with considerable variation in age at onset and severity of spasticity. There are also complex forms of HSP, with additional neurological features or extra‐neurological signs. HSPs are transmitted according to all modes of inheritance, and 21 of the 43 genes localised have been identified. In recent years, genetic studies have shown abnormal membrane trafficking, axonal transport, cholesterol homeostasis and mitochondrial dysfunction to be the major physiopathological mechanisms in HSP. A new classification is now emerging taking into account clinical, genetic and pathological mechanisms. Key Concepts: Hereditary spastic paraplegias are among the most highly heterogeneous neurodegenerative disorders. The clinical presentation in patients can be pure or complex, variably associating additional, neurological and non‐neurological signs. Mutations or genomic rearrangements in at least 43 genes can lead to spastic paraplegia. Intracellular trafficking and maintenance of axon/myelin are the main systems altered in these diseases.

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The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo

Cited by 134 publications

References 46 publications

Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia

Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia

Pathogenic Mutation of Spastin Has Gain-of-Function Effects on Microtubule Dynamics

Molecular Genetics of Hereditary Spastic Paraplegias

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