Presenilin/γ-secretase-dependent epha3 processing mediates axon elongation through non-muscle myosin IIA

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 Rho...

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Detalles Bibliográficos
Autores: Javier, Miriam|||0000-0002-6437-2829, Marco, Sergi|||0000-0002-9747-0388, Rocandio, Daniel, Pons Vizcarra, Maria|||0000-0001-5008-5741, Janes, Peter W., Lackmann, Martin, Egea, Joaquim, Saura Antolín, Carlos|||0000-0003-3692-5657
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:223754
Acceso en línea:https://ddd.uab.cat/record/223754
https://dx.doi.org/urn:doi:10.7554/eLife.43646
Access Level:acceso abierto
Palabra clave:Animals
Axons
Cells, Cultured
Humans
Mice
Nonmuscle Myosin Type IIA
Presenilin-1
Receptor, EphA3
Rhoa GTP-Binding Protein
Signal Transduction
Descripción
Sumario: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.

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