BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.
View / Open Files
Authors
Giudicelli, François
Ten Martín, Daniel
Vitrac, Anaïs
De Gois, Stéphanie
Allison, Rachel
Hazan, Jamilé
Publication Date
2018-09-12Journal Title
Development
ISSN
0950-1991
Publisher
The Company of Biologists
Volume
145
Issue
17
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
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
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.
Keywords
Axon navigation, BMP signalling, Hereditary spastic paraplegia, Neuropilin 1, Spastin, Zebrafish, Animals, Axons, Bone Morphogenetic Proteins, COS Cells, CRISPR-Cas Systems, Cell Line, Cell Movement, Chlorocebus aethiops, GTP-Binding Proteins, Gene Knockout Techniques, Humans, Membrane Proteins, Motor Neurons, Neuropilin-1, Protein Isoforms, Spastic Paraplegia, Hereditary, Spastin, Zebrafish, Zebrafish Proteins
Sponsorship
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
Funder references
Medical Research Council (MR/M00046X/1)
Identifiers
External DOI: https://doi.org/10.1242/dev.162701
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284535
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk