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Development. 2018 Sep 12;145(17). pii: dev162701. doi: 10.1242/dev.162701.

BMP- and neuropilin 1-mediated motor axon navigation relies on spastin alternative translation.

Author information

1
Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Neuroscience Paris Seine - Institut de Biologie Paris-Seine (NPS-IBPS), 75005 Paris, France.
2
Sorbonne Universités, UPMC Université Paris 06, CNRS, INSERM, Biologie du Développement Paris Seine - Institut de Biologie Paris-Seine (LBD-IBPS), 75005 Paris, France.
3
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK.
4
Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 1UL, UK.
5
Sorbonne Universités, UPMC Université Paris 06, INSERM, CNRS, Neuroscience Paris Seine - Institut de Biologie Paris-Seine (NPS-IBPS), 75005 Paris, France coralie.fassier@upmc.fr jamile.hazan@upmc.fr.

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

PMID:
30082270
PMCID:
PMC6141775
DOI:
10.1242/dev.162701
[Indexed for MEDLINE]
Free PMC Article

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