| RRC ID |
76514
|
| Author |
Jardin N, Giudicelli F, Ten Martín D, Vitrac A, De Gois S, Allison R, Houart C, Reid E, Hazan J, Fassier C.
|
| Title |
BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.
|
| Journal |
Development
|
| Abstract |
Functional analyses of genes responsible for neurodegenerative disorders have unveiled crucial links between neurodegenerative processes and key developmental signalling pathways. Mutations in SPG4-encoding spastin cause hereditary spastic paraplegia (HSP). Spastin is involved in diverse cellular processes that couple microtubule severing to membrane remodelling. Two main spastin isoforms are synthesised from alternative translational start sites (M1 and M87). However, their specific roles in neuronal development and homeostasis remain largely unknown. To selectively unravel their neuronal function, we blocked spastin synthesis from each initiation codon during zebrafish development and performed rescue analyses. The knockdown of each isoform led to different motor neuron and locomotion defects, which were not rescued by the selective expression of the other isoform. Notably, both morphant neuronal phenotypes were observed in a CRISPR/Cas9 spastin mutant. We next showed that M1 spastin, together with HSP proteins atlastin 1 and NIPA1, drives motor axon targeting by repressing BMP signalling, whereas M87 spastin acts downstream of neuropilin 1 to control motor neuron migration. Our data therefore suggest that defective BMP and neuropilin 1 signalling may contribute to the motor phenotype in a vertebrate model of spastin depletion.
|
| Volume |
145(17)
|
| Published |
2018-9-12
|
| DOI |
10.1242/dev.162701
|
| PII |
dev.162701
|
| PMID |
30082270
|
| PMC |
PMC6141775
|
| MeSH |
Animals
Axons / metabolism
Bone Morphogenetic Proteins / metabolism*
COS Cells
CRISPR-Cas Systems / genetics
Cell Line
Cell Movement / genetics
Chlorocebus aethiops
GTP-Binding Proteins / metabolism
Gene Knockout Techniques
Humans
Membrane Proteins / metabolism
Motor Neurons / cytology*
Neuropilin-1 / metabolism*
Protein Isoforms / genetics
Spastic Paraplegia, Hereditary / genetics
Spastin / biosynthesis
Spastin / genetics*
Zebrafish / embryology*
Zebrafish Proteins / biosynthesis
Zebrafish Proteins / genetics*
|
| IF |
5.611
|
| Resource |
| Zebrafish |
mnGFF7, UAS:GFP |
