| First Author | Javier-Torrent M | Year | 2019 |
| Journal | Elife | Volume | 8 |
| PubMed ID | 31577226 | Mgi Jnum | J:290203 |
| Mgi Id | MGI:6435927 | Doi | 10.7554/eLife.43646 |
| Citation | Javier-Torrent M, et al. (2019) Presenilin/gamma-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA. Elife 8:e43646 |
| abstractText | 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)/gamma-secretase is required for axon growth in the developing mouse brain. PS1/gamma-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/gamma-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/gamma-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/gamma-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. |
