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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Autores: Javier-Torrent, Míriam, Marco, Sergio, Rocandio Durán, Daniel, Pons-Vizcarra, Maria, Janes, Peter W, Lackmann, Martin, Egea Navarro, Joaquim, Saura, Carlos A
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/68213
Acceso en línea:https://doi.org/10.7554/eLife.43646
http://hdl.handle.net/10459.1/68213
Access Level:acceso abierto
Palabra clave:Neurociències
Neurones
Axons
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spelling Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIAPresenilin/gamma-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIAJavier-Torrent, MíriamMarco, SergioRocandio Durán, DanielPons-Vizcarra, MariaJanes, Peter WLackmann, MartinEgea Navarro, JoaquimSaura, Carlos ANeurociènciesNeuronesAxonsEphA/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.Ministerio de Economia y Competitividad SAF2013-43900-R Carlos A Saura, Ministerio de Economia y Competitividad SAF2016-80027-R Carlos A Saura, Ministerio de Economia y Competitividad CIBERNED CB06/05/0042 Carlos A Saura Generalitat de Catalunya ICREA Academia Carlos A Saura, Generalitat de Catalunya 2017 SGR749 Carlos A Saura.eLife Sciences Publications202020202019info:eu-repo/semantics/articlehttps://doi.org/10.7554/eLife.43646http://hdl.handle.net/10459.1/68213http://hdl.handle.net/10459.1/68213reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésMINECO/PN2013-2016/SAF2013-43900-RMINECO/PN2013-2016/SAF2016-80027-RReproducció del document publicat a https://doi.org/10.7554/eLife.43646eLife, 2019, vol. 8cc-by, (c) Javier-Torrent et al., 2019info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:recercat.cat:10459.1/682132026-05-29T05:05:01Z
dc.title.none.fl_str_mv Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
Presenilin/gamma-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
title Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
spellingShingle Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
Javier-Torrent, Míriam
Neurociències
Neurones
Axons
title_short Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
title_full Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
title_fullStr Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
title_full_unstemmed Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
title_sort Presenilin/γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
dc.creator.none.fl_str_mv Javier-Torrent, Míriam
Marco, Sergio
Rocandio Durán, Daniel
Pons-Vizcarra, Maria
Janes, Peter W
Lackmann, Martin
Egea Navarro, Joaquim
Saura, Carlos A
author Javier-Torrent, Míriam
author_facet Javier-Torrent, Míriam
Marco, Sergio
Rocandio Durán, Daniel
Pons-Vizcarra, Maria
Janes, Peter W
Lackmann, Martin
Egea Navarro, Joaquim
Saura, Carlos A
author_role author
author2 Marco, Sergio
Rocandio Durán, Daniel
Pons-Vizcarra, Maria
Janes, Peter W
Lackmann, Martin
Egea Navarro, Joaquim
Saura, Carlos A
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Neurociències
Neurones
Axons
topic Neurociències
Neurones
Axons
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://doi.org/10.7554/eLife.43646
http://hdl.handle.net/10459.1/68213
http://hdl.handle.net/10459.1/68213
url https://doi.org/10.7554/eLife.43646
http://hdl.handle.net/10459.1/68213
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv MINECO/PN2013-2016/SAF2013-43900-R
MINECO/PN2013-2016/SAF2016-80027-R
Reproducció del document publicat a https://doi.org/10.7554/eLife.43646
eLife, 2019, vol. 8
dc.rights.none.fl_str_mv cc-by, (c) Javier-Torrent et al., 2019
info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv cc-by, (c) Javier-Torrent et al., 2019
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv eLife Sciences Publications
publisher.none.fl_str_mv eLife Sciences Publications
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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