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Mice with the progressive motor neuronopathy (pmn) mutation develop a degenerative and fatal motoneuron disease shortly after birth, making them a popular animal model for studying human neurodegenerative diseases such as spinal muscular atrophy. Two independent reports (B?mmel et al., page 563; Martin, N., et al. 2002. Nat. Genet. 32:443–447) now identify the genetic defect in pmn mice as a point mutation in a gene for a tubulin-specific chaperone. The result suggests that motoneuron axons, which can reach lengths of greater than one meter in adult humans, may put unusual demands on the microtubule cytoskeleton.
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Fine-scale mapping and sequencing revealed a single missense mutation in the Tbce gene in pmn mice, resulting in the substitution of tryptophan for glycine in the tubulin-specific chaperone protein CofE. The wild-type glycine residue is strictly conserved among vertebrates, raising the possibility that a similar defect may be responsible for some of the unexplained sporadic cases of human motoneuron diseases.! `$ X5 u% d- @( n
" l/ b- f$ L% G! O( R& b0 v+ eAfter identifying the mutation, B?mmel et al. isolated and cultured motoneurons from embryonic pmn and wild-type mice, and found that the mutant neurons grow shorter axons and exhibit axonal swellings. The pmn motoneurons appear to survive as well as wild-type motoneurons, suggesting that the condition seen in the mutant mice is a consequence of axonal defects rather than neuronal death.: D$ n, V" j% d& D
* u) a8 a. d6 d+ [The findings suggest a relatively straightforward explanation for the pmn phenotype: a defective microtubule chaperone protein could interfere with the proper assembly of the microtubule heterodimers required for normal axonal transport, leading to shorter axons. Microtubules are also essential for fundamental cellular processes such as mitotic spindle assembly, so it is unclear how pmn mutant mice manage to develop normally. One possibility is that neuron-specific isoforms of tubulin may have a more stringent requirement for CofE during assembly.(Mutant spinal neurons (right) have short) |
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发表于 2009-3-6 00:14
发表于 2015-6-11 16:44
