Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development

Autores
Romero, Delfina Mercedes; Poirier, Karine; Belvindrah, Richard; Moutkine, Imane; Houllier, Anne; LeMoing, Anne Gaëlle; Petit, Florence; Boland, Anne; Collins, Stephan C.; Soiza Reilly, Mariano; Yalcin, Binnaz; Chelly, Jamel; Deleuze, Jean François; Bahi Buisson, Nadia; Francis, Fiona
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
Fil: Romero, Delfina Mercedes. Inserm; Francia. Sorbonne University; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina
Fil: Poirier, Karine. Inserm; Francia
Fil: Belvindrah, Richard. Sorbonne University; Francia. Inserm; Francia
Fil: Moutkine, Imane. Sorbonne University; Francia. Inserm; Francia
Fil: Houllier, Anne. Inserm; Francia. Sorbonne University; Francia
Fil: LeMoing, Anne Gaëlle. No especifíca;
Fil: Petit, Florence. Hôpital Jeanne de Flandre; Francia
Fil: Boland, Anne. Universite Paris-Saclay;
Fil: Collins, Stephan C.. Inserm; Francia
Fil: Soiza Reilly, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Yalcin, Binnaz. Inserm; Francia
Fil: Chelly, Jamel. Inserm; Francia
Fil: Deleuze, Jean François. Universite Paris-Saclay;
Fil: Bahi Buisson, Nadia. Inserm; Francia
Fil: Francis, Fiona. Sorbonne University; Francia. Inserm; Francia
Materia
MALFORMATIONS
CORTICAL DEVELOPMENT
MUTATIONS
GLIAL PROGENITORS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/214543
Acceder
id CONICETDig_6631be95b49459aa38a15d74dc7d9895
oai_identifier_str oai:ri.conicet.gov.ar:11336/214543
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical developmentRomero, Delfina MercedesPoirier, KarineBelvindrah, RichardMoutkine, ImaneHoullier, AnneLeMoing, Anne GaëllePetit, FlorenceBoland, AnneCollins, Stephan C.Soiza Reilly, MarianoYalcin, BinnazChelly, JamelDeleuze, Jean FrançoisBahi Buisson, NadiaFrancis, FionaMALFORMATIONSCORTICAL DEVELOPMENTMUTATIONSGLIAL PROGENITORShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.Fil: Romero, Delfina Mercedes. Inserm; Francia. Sorbonne University; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Poirier, Karine. Inserm; FranciaFil: Belvindrah, Richard. Sorbonne University; Francia. Inserm; FranciaFil: Moutkine, Imane. Sorbonne University; Francia. Inserm; FranciaFil: Houllier, Anne. Inserm; Francia. Sorbonne University; FranciaFil: LeMoing, Anne Gaëlle. No especifíca;Fil: Petit, Florence. Hôpital Jeanne de Flandre; FranciaFil: Boland, Anne. Universite Paris-Saclay;Fil: Collins, Stephan C.. Inserm; FranciaFil: Soiza Reilly, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Yalcin, Binnaz. Inserm; FranciaFil: Chelly, Jamel. Inserm; FranciaFil: Deleuze, Jean François. Universite Paris-Saclay;Fil: Bahi Buisson, Nadia. Inserm; FranciaFil: Francis, Fiona. Sorbonne University; Francia. Inserm; FranciaNature2022-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/214543Romero, Delfina Mercedes; Poirier, Karine; Belvindrah, Richard; Moutkine, Imane; Houllier, Anne; et al.; Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development; Nature; Nature Communications; 13; 1; 5-2022; 1-192041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-022-30443-zinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:24:22Zoai:ri.conicet.gov.ar:11336/214543instacron: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 14:24:22.508CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
title Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
spellingShingle Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
Romero, Delfina Mercedes
MALFORMATIONS
CORTICAL DEVELOPMENT
MUTATIONS
GLIAL PROGENITORS
title_short Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
title_full Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
title_fullStr Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
title_full_unstemmed Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
title_sort Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development
dc.creator.none.fl_str_mv Romero, Delfina Mercedes
Poirier, Karine
Belvindrah, Richard
Moutkine, Imane
Houllier, Anne
LeMoing, Anne Gaëlle
Petit, Florence
Boland, Anne
Collins, Stephan C.
Soiza Reilly, Mariano
Yalcin, Binnaz
Chelly, Jamel
Deleuze, Jean François
Bahi Buisson, Nadia
Francis, Fiona
author Romero, Delfina Mercedes
author_facet Romero, Delfina Mercedes
Poirier, Karine
Belvindrah, Richard
Moutkine, Imane
Houllier, Anne
LeMoing, Anne Gaëlle
Petit, Florence
Boland, Anne
Collins, Stephan C.
Soiza Reilly, Mariano
Yalcin, Binnaz
Chelly, Jamel
Deleuze, Jean François
Bahi Buisson, Nadia
Francis, Fiona
author_role author
author2 Poirier, Karine
Belvindrah, Richard
Moutkine, Imane
Houllier, Anne
LeMoing, Anne Gaëlle
Petit, Florence
Boland, Anne
Collins, Stephan C.
Soiza Reilly, Mariano
Yalcin, Binnaz
Chelly, Jamel
Deleuze, Jean François
Bahi Buisson, Nadia
Francis, Fiona
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MALFORMATIONS
CORTICAL DEVELOPMENT
MUTATIONS
GLIAL PROGENITORS
topic MALFORMATIONS
CORTICAL DEVELOPMENT
MUTATIONS
GLIAL PROGENITORS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
Fil: Romero, Delfina Mercedes. Inserm; Francia. Sorbonne University; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; Argentina
Fil: Poirier, Karine. Inserm; Francia
Fil: Belvindrah, Richard. Sorbonne University; Francia. Inserm; Francia
Fil: Moutkine, Imane. Sorbonne University; Francia. Inserm; Francia
Fil: Houllier, Anne. Inserm; Francia. Sorbonne University; Francia
Fil: LeMoing, Anne Gaëlle. No especifíca;
Fil: Petit, Florence. Hôpital Jeanne de Flandre; Francia
Fil: Boland, Anne. Universite Paris-Saclay;
Fil: Collins, Stephan C.. Inserm; Francia
Fil: Soiza Reilly, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Yalcin, Binnaz. Inserm; Francia
Fil: Chelly, Jamel. Inserm; Francia
Fil: Deleuze, Jean François. Universite Paris-Saclay;
Fil: Bahi Buisson, Nadia. Inserm; Francia
Fil: Francis, Fiona. Sorbonne University; Francia. Inserm; Francia
description Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
publishDate 2022
dc.date.none.fl_str_mv 2022-05
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/11336/214543
Romero, Delfina Mercedes; Poirier, Karine; Belvindrah, Richard; Moutkine, Imane; Houllier, Anne; et al.; Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development; Nature; Nature Communications; 13; 1; 5-2022; 1-19
2041-1723
CONICET Digital
CONICET
url http://hdl.handle.net/11336/214543
identifier_str_mv Romero, Delfina Mercedes; Poirier, Karine; Belvindrah, Richard; Moutkine, Imane; Houllier, Anne; et al.; Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development; Nature; Nature Communications; 13; 1; 5-2022; 1-19
2041-1723
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/s41467-022-30443-z
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
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 12.891075

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