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

Functional analyses of genes responsible for neurodegenerative disorders have unveiled critical 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 coupling 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 motoneuron 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 show that M1 spastin together with HSP proteins atlastin-1 and NIPA1 drive motor axon targeting by repressing BMP signalling, while M87 spastin acts downstream Neuropilin-1 to control motoneuron migration. Our data thus suggest that defective BMP and Neuropilin-1 signalling may contribute to the motor phenotype in a vertebrate model of spastin depletion.