BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.
Ten Martín, Daniel
De Gois, Stéphanie
The Company of Biologists
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Jardin, N., Giudicelli, F., Ten Martín, D., Vitrac, A., De Gois, S., Allison, R., Houart, C., et al. (2018). BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.. Development, 145 (17) https://doi.org/10.1242/dev.162701
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.
Axons, Motor Neurons, Cell Line, COS Cells, Animals, Zebrafish, Humans, Spastic Paraplegia, Hereditary, GTP-Binding Proteins, Zebrafish Proteins, Bone Morphogenetic Proteins, Membrane Proteins, Neuropilin-1, Protein Isoforms, Cell Movement, Gene Knockout Techniques, CRISPR-Cas Systems, Spastin, Chlorocebus aethiops
See acknowledgements in paper. In addition, the following funder statement has been added to the acknowledgements section of the paper at the proof stage (and is not in the attached manuscript file): ER and RA are supported by grant MR/M00046X/1 from the UK Medical Research Council
Medical Research Council (MR/M00046X/1)
External DOI: https://doi.org/10.1242/dev.162701
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284535
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/