Presenilin/γ-secretase-dependent epha3 processing mediates axon elongation through non-muscle myosin IIA
Javier, Miriam (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Marco, Sergi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Rocandio, Daniel (Institut de Recerca Biomèdica de Lleida)
Pons Vizcarra, Maria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Janes, Peter W. (Tumour Targeting Program. Olivia Newton-John Cancer Research Institute)
Lackmann, Martin (Department of Biochemistry and Molecular Biology. Monash University)
Egea, Joaquim (Institut de Recerca Biomèdica de Lleida)
Saura Antolín, Carlos (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2019
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.
Grants:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-749 Ministerio de Economía y Competitividad SAF2013-43900-R Ministerio de Economía y Competitividad SAF2016-80027-R Ministerio de Economía y Competitividad CB06/05/0042
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Animals ; Axons ; Cells, Cultured ; Humans ; Mice ; Nonmuscle Myosin Type IIA ; Presenilin-1 ; Receptor, EphA3 ; Rhoa GTP-Binding Protein ; Signal Transduction
Published in:	eLife, Vol. 8 (october 2019) , p. e43646, ISSN 2050-084X

DOI: 10.7554/eLife.43646
PMID: 31577226

26 p, 9.8 MB

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