Progressive motor neuronopathy (pmn) mutant mice have been widely used as a model for human motoneuron disease. Mice that are homozygous for the pmn gene defect appear healthy at birth but develop progressive motoneuron disease, resulting in severe skeletal muscle weakness and respiratory failure by postnatal week 3. The disease starts at the motor endplates, and then leads to axonal loss and finally to apoptosis of the corresponding cell bodies. We localized the genetic defect in pmn mice to a missense mutation in the tubulin-specific chaperone E (Tbce) gene on mouse chromosome 13. The human orthologue maps to chromosome 1q42.3. The Tbce gene encodes a protein (cofactor E) that is essential for the formation of primary α-tubulin and β-tubulin heterodimeric complexes. Isolated motoneurons from pmn mutant mice exhibit shorter axons and axonal swelling with irregularly structured β-tubulin and tau immunoreactivity. Thus, the pmn gene mutation provides the first genetic evidence that alterations in tubulin assembly lead to retrograde degeneration of motor axons, ultimately resulting in motoneuron cell death.
Missense mutation in the tubulin-specific chaperone E (Tbce) gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron disease
The online version of this article includes supplemental material.
H. Bömmel and G. Xie contributed equally to this work.
G. Xie's present address is Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Canada.
Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; BAC, bacterial artificial chromosome; CofE, cofactor E; pmn, progressive motor neuronopathy; SMA, spinal muscular atrophy; SMARD1, SMA with respiratory distress type 1; STS, sequence-tagged site; Tbce, tubulin-specific chaperone E; wt, wild type; YAC, yeast artificial chromosome.
Heike Bömmel, Gang Xie, Wilfried Rossoll, Stefan Wiese, Sibylle Jablonka, Thomas Boehm, Michael Sendtner; Missense mutation in the tubulin-specific chaperone E (Tbce) gene in the mouse mutant progressive motor neuronopathy, a model of human motoneuron disease . J Cell Biol 25 November 2002; 159 (4): 563–569. doi: https://doi.org/10.1083/jcb.200208001
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