Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways

Autores
Palandri, Anabela; Rozés Salvador, María Victoria; Wojnacki Fonseca, José Ignacio; Vivinetto, Ana Laura; Schnaar, R. L.; Lopez Piñeyro, Hernán Ignacio
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Myelin-associated glycoprotein (MAG) is a minor constituent of nervous system myelin, selectively expressed on the periaxonal myelin wrap. By engaging multiple axonal receptors, including Nogo-receptors (NgRs), MAG exerts a nurturing and protective effect the axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75 NTR -dependent postnatal apoptosis of motoneurons (MNs). However, it is not clear whether this reflects a physiological role of NgRs in MN development. NgRs are part of a multimeric receptor complex, which includes p75 NTR, Lingo-1 and gangliosides. Upon ligand binding, this multimeric complex activates RhoA/ROCK signaling in a p75 NTR -dependent manner. The aim of this study was to analyze a possible modulatory role of MAG on MN apoptosis during postnatal development. A time course study showed that Mag-null mice suffer a loss of MNs during the first postnatal week. Also, these mice exhibited increased susceptibility in an animal model of p75 NTR -dependent MN apoptosis induced by nerve-crush injury, which was prevented by treatment with a soluble form of MAG (MAG-Fc). The protective role of MAG was confirmed in in vitro models of p75 NTR -dependent MN apoptosis using the MN1 cell line and primary cultures. Lentiviral expression of shRNA sequences targeting NgRs on these cells abolished protection by MAG-Fc. Analysis of RhoA activity using a FRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75 NTR /RhoA/ROCK pathway, or overexpression of a p75 NTR mutant unable to activate RhoA, completely blocked MAG-Fc protection against apoptosis. The role of RhoA/ROCK signaling was further confirmed in the nerve-crush model, where pretreatment with ROCK inhibitor Y-27632 blocked the pro-survival effect of MAG-Fc. These findings identify a new protective role of MAG as a modulator of apoptosis of MNs during postnatal development by a mechanism involving the p75 NTR /RhoA/ROCK signaling pathway. Also, our results highlight the relevance of the nurture/protective effects of myelin on neurons.
Fil: Palandri, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Rozés Salvador, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Wojnacki Fonseca, José Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Vivinetto, Ana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Schnaar, R. L.. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Lopez Piñeyro, Hernán Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina
Materia
myelin-associated glycoprotein
apoptosis
motoneurons
p75(NTR)
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/69413
Acceder
id CONICETDig_fc08840a75b20f980e51cdb4dec5b221
oai_identifier_str oai:ri.conicet.gov.ar:11336/69413
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathwaysPalandri, AnabelaRozés Salvador, María VictoriaWojnacki Fonseca, José IgnacioVivinetto, Ana LauraSchnaar, R. L.Lopez Piñeyro, Hernán Ignaciomyelin-associated glycoproteinapoptosismotoneuronsp75(NTR)https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Myelin-associated glycoprotein (MAG) is a minor constituent of nervous system myelin, selectively expressed on the periaxonal myelin wrap. By engaging multiple axonal receptors, including Nogo-receptors (NgRs), MAG exerts a nurturing and protective effect the axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75 NTR -dependent postnatal apoptosis of motoneurons (MNs). However, it is not clear whether this reflects a physiological role of NgRs in MN development. NgRs are part of a multimeric receptor complex, which includes p75 NTR, Lingo-1 and gangliosides. Upon ligand binding, this multimeric complex activates RhoA/ROCK signaling in a p75 NTR -dependent manner. The aim of this study was to analyze a possible modulatory role of MAG on MN apoptosis during postnatal development. A time course study showed that Mag-null mice suffer a loss of MNs during the first postnatal week. Also, these mice exhibited increased susceptibility in an animal model of p75 NTR -dependent MN apoptosis induced by nerve-crush injury, which was prevented by treatment with a soluble form of MAG (MAG-Fc). The protective role of MAG was confirmed in in vitro models of p75 NTR -dependent MN apoptosis using the MN1 cell line and primary cultures. Lentiviral expression of shRNA sequences targeting NgRs on these cells abolished protection by MAG-Fc. Analysis of RhoA activity using a FRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75 NTR /RhoA/ROCK pathway, or overexpression of a p75 NTR mutant unable to activate RhoA, completely blocked MAG-Fc protection against apoptosis. The role of RhoA/ROCK signaling was further confirmed in the nerve-crush model, where pretreatment with ROCK inhibitor Y-27632 blocked the pro-survival effect of MAG-Fc. These findings identify a new protective role of MAG as a modulator of apoptosis of MNs during postnatal development by a mechanism involving the p75 NTR /RhoA/ROCK signaling pathway. Also, our results highlight the relevance of the nurture/protective effects of myelin on neurons.Fil: Palandri, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Rozés Salvador, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Wojnacki Fonseca, José Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Vivinetto, Ana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Schnaar, R. L.. Johns Hopkins University School of Medicine; Estados UnidosFil: Lopez Piñeyro, Hernán Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; ArgentinaNature Publishing Group2015-09info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/69413Palandri, Anabela; Rozés Salvador, María Victoria; Wojnacki Fonseca, José Ignacio; Vivinetto, Ana Laura; Schnaar, R. L.; et al.; Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways; Nature Publishing Group; Cell Death and Disease; 6; 9-2015; 1-122041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/cddis.2015.228info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cddis2015228info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:23:24Zoai:ri.conicet.gov.ar:11336/69413instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:23:25.011CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
title Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
spellingShingle Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
Palandri, Anabela
myelin-associated glycoprotein
apoptosis
motoneurons
p75(NTR)
title_short Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
title_full Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
title_fullStr Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
title_full_unstemmed Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
title_sort Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways
dc.creator.none.fl_str_mv Palandri, Anabela
Rozés Salvador, María Victoria
Wojnacki Fonseca, José Ignacio
Vivinetto, Ana Laura
Schnaar, R. L.
Lopez Piñeyro, Hernán Ignacio
author Palandri, Anabela
author_facet Palandri, Anabela
Rozés Salvador, María Victoria
Wojnacki Fonseca, José Ignacio
Vivinetto, Ana Laura
Schnaar, R. L.
Lopez Piñeyro, Hernán Ignacio
author_role author
author2 Rozés Salvador, María Victoria
Wojnacki Fonseca, José Ignacio
Vivinetto, Ana Laura
Schnaar, R. L.
Lopez Piñeyro, Hernán Ignacio
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv myelin-associated glycoprotein
apoptosis
motoneurons
p75(NTR)
topic myelin-associated glycoprotein
apoptosis
motoneurons
p75(NTR)
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Myelin-associated glycoprotein (MAG) is a minor constituent of nervous system myelin, selectively expressed on the periaxonal myelin wrap. By engaging multiple axonal receptors, including Nogo-receptors (NgRs), MAG exerts a nurturing and protective effect the axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75 NTR -dependent postnatal apoptosis of motoneurons (MNs). However, it is not clear whether this reflects a physiological role of NgRs in MN development. NgRs are part of a multimeric receptor complex, which includes p75 NTR, Lingo-1 and gangliosides. Upon ligand binding, this multimeric complex activates RhoA/ROCK signaling in a p75 NTR -dependent manner. The aim of this study was to analyze a possible modulatory role of MAG on MN apoptosis during postnatal development. A time course study showed that Mag-null mice suffer a loss of MNs during the first postnatal week. Also, these mice exhibited increased susceptibility in an animal model of p75 NTR -dependent MN apoptosis induced by nerve-crush injury, which was prevented by treatment with a soluble form of MAG (MAG-Fc). The protective role of MAG was confirmed in in vitro models of p75 NTR -dependent MN apoptosis using the MN1 cell line and primary cultures. Lentiviral expression of shRNA sequences targeting NgRs on these cells abolished protection by MAG-Fc. Analysis of RhoA activity using a FRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75 NTR /RhoA/ROCK pathway, or overexpression of a p75 NTR mutant unable to activate RhoA, completely blocked MAG-Fc protection against apoptosis. The role of RhoA/ROCK signaling was further confirmed in the nerve-crush model, where pretreatment with ROCK inhibitor Y-27632 blocked the pro-survival effect of MAG-Fc. These findings identify a new protective role of MAG as a modulator of apoptosis of MNs during postnatal development by a mechanism involving the p75 NTR /RhoA/ROCK signaling pathway. Also, our results highlight the relevance of the nurture/protective effects of myelin on neurons.
Fil: Palandri, Anabela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Rozés Salvador, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Wojnacki Fonseca, José Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Vivinetto, Ana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Schnaar, R. L.. Johns Hopkins University School of Medicine; Estados Unidos
Fil: Lopez Piñeyro, Hernán Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina
description Myelin-associated glycoprotein (MAG) is a minor constituent of nervous system myelin, selectively expressed on the periaxonal myelin wrap. By engaging multiple axonal receptors, including Nogo-receptors (NgRs), MAG exerts a nurturing and protective effect the axons it ensheaths. Pharmacological activation of NgRs has a modulatory role on p75 NTR -dependent postnatal apoptosis of motoneurons (MNs). However, it is not clear whether this reflects a physiological role of NgRs in MN development. NgRs are part of a multimeric receptor complex, which includes p75 NTR, Lingo-1 and gangliosides. Upon ligand binding, this multimeric complex activates RhoA/ROCK signaling in a p75 NTR -dependent manner. The aim of this study was to analyze a possible modulatory role of MAG on MN apoptosis during postnatal development. A time course study showed that Mag-null mice suffer a loss of MNs during the first postnatal week. Also, these mice exhibited increased susceptibility in an animal model of p75 NTR -dependent MN apoptosis induced by nerve-crush injury, which was prevented by treatment with a soluble form of MAG (MAG-Fc). The protective role of MAG was confirmed in in vitro models of p75 NTR -dependent MN apoptosis using the MN1 cell line and primary cultures. Lentiviral expression of shRNA sequences targeting NgRs on these cells abolished protection by MAG-Fc. Analysis of RhoA activity using a FRET-based RhoA biosensor showed that MAG-Fc activates RhoA. Pharmacological inhibition of p75 NTR /RhoA/ROCK pathway, or overexpression of a p75 NTR mutant unable to activate RhoA, completely blocked MAG-Fc protection against apoptosis. The role of RhoA/ROCK signaling was further confirmed in the nerve-crush model, where pretreatment with ROCK inhibitor Y-27632 blocked the pro-survival effect of MAG-Fc. These findings identify a new protective role of MAG as a modulator of apoptosis of MNs during postnatal development by a mechanism involving the p75 NTR /RhoA/ROCK signaling pathway. Also, our results highlight the relevance of the nurture/protective effects of myelin on neurons.
publishDate 2015
dc.date.none.fl_str_mv 2015-09
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/69413
Palandri, Anabela; Rozés Salvador, María Victoria; Wojnacki Fonseca, José Ignacio; Vivinetto, Ana Laura; Schnaar, R. L.; et al.; Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways; Nature Publishing Group; Cell Death and Disease; 6; 9-2015; 1-12
2041-4889
CONICET Digital
CONICET
url http://hdl.handle.net/11336/69413
identifier_str_mv Palandri, Anabela; Rozés Salvador, María Victoria; Wojnacki Fonseca, José Ignacio; Vivinetto, Ana Laura; Schnaar, R. L.; et al.; Myelin-associated glycoprotein modulates apoptosis of motoneurons during early postnatal development via NgR/p75 NTR receptor-mediated activation of RhoA signaling pathways; Nature Publishing Group; Cell Death and Disease; 6; 9-2015; 1-12
2041-4889
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1038/cddis.2015.228
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cddis2015228
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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