PUBLICATION
Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia
- Authors
- Butler, R., Wood, J.D., Landers, J.A., and Cunliffe, V.T.
- ID
- ZDB-PUB-100929-7
- Date
- 2010
- Source
- Disease models & mechanisms 3(11-12): 743-751 (Journal)
- Registered Authors
- Cunliffe, Vincent
- Keywords
- none
- MeSH Terms
-
- Adenosine Triphosphatases/genetics*
- Adenosine Triphosphatases/metabolism*
- Animals
- Axons/drug effects
- Axons/metabolism*
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/enzymology*
- Gene Knockdown Techniques
- Green Fluorescent Proteins/metabolism
- Growth Cones/drug effects
- Growth Cones/pathology
- Microtubule-Associated Proteins/metabolism
- Microtubules/drug effects
- Microtubules/pathology*
- Models, Biological
- Motor Neurons/drug effects
- Motor Neurons/enzymology
- Motor Neurons/pathology
- Nocodazole/pharmacology
- Oligonucleotides, Antisense/pharmacology
- Phenotype
- RNA Splicing/drug effects
- RNA Splicing/genetics
- Spastic Paraplegia, Hereditary/enzymology*
- Spastic Paraplegia, Hereditary/pathology
- Zebrafish/embryology*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism*
- PubMed
- 20829563 Full text @ Dis. Model. Mech.
Citation
Butler, R., Wood, J.D., Landers, J.A., and Cunliffe, V.T. (2010) Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia. Disease models & mechanisms. 3(11-12):743-751.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping