| RRC ID |
2453
|
| 著者 |
Wood JD, Landers JA, Bingley M, McDermott CJ, Thomas-McArthur V, Gleadall LJ, Shaw PJ, Cunliffe VT.
|
| タイトル |
The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo.
|
| ジャーナル |
Hum Mol Genet
|
| Abstract |
Hereditary spastic paraplegia (HSP) is a collection of neurological disorders characterized by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity. SPG4 mutations are the most common cause of autosomal dominant HSP and Spastin (the SPG4 gene product) is a microtubule severing protein that shares homology with katanin, the microtubule severing activity of which promotes axon growth in cultured neurons. Given the sequence and functional similarity between spastin and katanin, we hypothesized that spastin promotes the dynamic disassembly and remodelling of microtubules required for robust, properly directed motor axon outgrowth. To investigate this hypothesis, we cloned the zebrafish spg4 orthologue and used morpholino antisense oligonucleotides directed against the translation start site and the intron 7-8 splice donor site to knock down spastin function in the developing zebrafish embryo. Reduced spg4 function caused dramatic defects in motor axon outgrowth without affecting the events driving the initial specification of motor neurones. Other neuronal subtypes also exhibited a requirement for spg4 function, since spg4 knock down caused both widespread defects in neuronal connectivity and extensive CNS-specific apoptosis. Our results reveal a critical requirement for spastin to promote axonal outgrowth during embryonic development, and they validate the zebrafish embryo as a novel model system to dissect the pathogenetic mechanisms underlying HSP. Taken together with other recent studies, our findings suggest that axon outgrowth defects may be a common feature of childhood SPG3A and SPG4 cases.
|
| 巻・号 |
15(18)
|
| ページ |
2763-71
|
| 公開日 |
2006-9-15
|
| DOI |
10.1093/hmg/ddl212
|
| PII |
ddl212
|
| PMID |
16893913
|
| MeSH |
Adenosine Triphosphatases / deficiency
Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism*
Animals
Axons / metabolism*
Base Sequence
Cloning, Molecular
DNA, Complementary / genetics
Humans
Microtubules / metabolism
Molecular Sequence Data
Motor Neurons / metabolism
Oligodeoxyribonucleotides, Antisense / genetics
Oligodeoxyribonucleotides, Antisense / pharmacology
Spastic Paraplegia, Hereditary / genetics
Spastic Paraplegia, Hereditary / metabolism
Synapses / metabolism
Zebrafish / embryology*
Zebrafish / genetics
Zebrafish / metabolism*
Zebrafish Proteins / deficiency
Zebrafish Proteins / genetics
Zebrafish Proteins / metabolism*
|
| IF |
5.101
|
| 引用数 |
94
|
|
WOS 分野
|
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ゼブラフィッシュ |
rw0 |
