Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA

Míriam Javier-Torrent, Sergi Marco, Daniel Rocandio, Maria Pons-Vizcarra, Peter W. Janes, Martin Lackmann, Joaquim Egea, Carlos A. Saura

Research output: Contribution to journalArticleResearch

1 Citation (Scopus)

Abstract

© 2019, Javier-Torrent et al. EphA/ephrin signaling regulates axon growth and guidance of neurons, but whether this process occurs also independently of ephrins is unclear. We show that presenilin-1 (PS1)/γ-secretase is required for axon growth in the developing mouse brain. PS1/γ-secretase mediates axon growth by inhibiting RhoA signaling and cleaving EphA3 independently of ligand to generate an intracellular domain (ICD) fragment that reverses axon defects in PS1/γ-secretase- and EphA3-deficient hippocampal neurons. Proteomic analysis revealed that EphA3 ICD binds to non-muscle myosin IIA (NMIIA) and increases its phosphorylation (Ser1943), which promotes NMIIA filament disassembly and cytoskeleton rearrangement. PS1/γ-secretase-deficient neurons show decreased phosphorylated NMIIA and NMIIA/actin colocalization. Moreover, pharmacological NMII inhibition reverses axon retraction in PS-deficient neurons suggesting that NMIIA mediates PS/EphA3-dependent axon elongation. In conclusion, PS/γ-secretase-dependent EphA3 cleavage mediates axon growth by regulating filament assembly through RhoA signaling and NMIIA, suggesting opposite roles of EphA3 on inhibiting (ligand-dependent) and promoting (receptor processing) axon growth in developing neurons.
Original languageEnglish
JournaleLife
Volume8
DOIs
Publication statusPublished - 2 Oct 2019

Keywords

  • EphA/ephrin signaling
  • PS/g-secretase
  • axon growth
  • mouse
  • neurons
  • neuroscience

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