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

Elife. 2019 Oct 2;8:e43646. doi: 10.7554/eLife.43646.

Abstract

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.

Keywords: EphA/ephrin signaling; PS/g-secretase; axon growth; mouse; neurons; neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / physiology*
  • Cells, Cultured
  • Humans
  • Mice
  • Nonmuscle Myosin Type IIA / metabolism*
  • Presenilin-1 / metabolism*
  • Receptor, EphA3 / metabolism*
  • Signal Transduction
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Presenilin-1
  • EPHA3 protein, human
  • Receptor, EphA3
  • Nonmuscle Myosin Type IIA
  • rhoA GTP-Binding Protein