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

Development. 2018 Sep 12;145(17):dev162701. doi: 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.

Keywords: Axon navigation; BMP signalling; Hereditary spastic paraplegia; Neuropilin 1; Spastin; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • Bone Morphogenetic Proteins
  • Membrane Proteins
  • NIPA1 protein, human
  • Protein Isoforms
  • Zebrafish Proteins
  • Neuropilin-1
  • ATL1 protein, human
  • GTP-Binding Proteins
  • Spastin
  • Spast protein, zebrafish