Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10216/110350 |
Resumo: | Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling. |
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Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelinationAnimalsCell Differentiation/physiologyChondrodysplasia Punctata Rhizomelic/etiologyChondrodysplasia Punctata Rhizomelic/pathologyChondrodysplasia Punctata Rhizomelic/physiopathologyFemaleGlycogen Synthase Kinase 3/antagonists & inhibitorsGlycogen Synthase Kinase 3/metabolismGlycogen Synthase Kinase 3 betaHumansMaleMiceMice KnockoutMice Neurologic MutantsModels NeurologicalMyelin Basic Protein/metabolismMyelin Sheath/physiologyNerve RegenerationPeripheral Nervous System/cytologyPeripheral Nervous System/physiologyPeroxisomal Targeting Signal 2 ReceptorPlasmalogens/physiologyProto-Oncogene Proteins c-akt/metabolismReceptors, Cytoplasmic and Nuclear/deficiencyReceptors, Cytoplasmic and Nuclear/geneticsSchwann Cells/cytologySchwann Cells/physiologySignal TransductionRhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.American Society for Clinical Investigation20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfapplication/pdfhttp://hdl.handle.net/10216/110350eng0021-973810.1172/JCI72063Silva, TFEira, JLopes, ATMalheiro, ARSousa, VLuoma, AAvila, RLWanders, RJJust, WWKirschner, DASousa, MMBrites, Pinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-29T13:39:45Zoai:repositorio-aberto.up.pt:10216/110350Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T23:45:03.276453Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
title |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
spellingShingle |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination Silva, TF Animals Cell Differentiation/physiology Chondrodysplasia Punctata Rhizomelic/etiology Chondrodysplasia Punctata Rhizomelic/pathology Chondrodysplasia Punctata Rhizomelic/physiopathology Female Glycogen Synthase Kinase 3/antagonists & inhibitors Glycogen Synthase Kinase 3/metabolism Glycogen Synthase Kinase 3 beta Humans Male Mice Mice Knockout Mice Neurologic Mutants Models Neurological Myelin Basic Protein/metabolism Myelin Sheath/physiology Nerve Regeneration Peripheral Nervous System/cytology Peripheral Nervous System/physiology Peroxisomal Targeting Signal 2 Receptor Plasmalogens/physiology Proto-Oncogene Proteins c-akt/metabolism Receptors, Cytoplasmic and Nuclear/deficiency Receptors, Cytoplasmic and Nuclear/genetics Schwann Cells/cytology Schwann Cells/physiology Signal Transduction |
title_short |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
title_full |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
title_fullStr |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
title_full_unstemmed |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
title_sort |
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination |
author |
Silva, TF |
author_facet |
Silva, TF Eira, J Lopes, AT Malheiro, AR Sousa, V Luoma, A Avila, RL Wanders, RJ Just, WW Kirschner, DA Sousa, MM Brites, P |
author_role |
author |
author2 |
Eira, J Lopes, AT Malheiro, AR Sousa, V Luoma, A Avila, RL Wanders, RJ Just, WW Kirschner, DA Sousa, MM Brites, P |
author2_role |
author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Silva, TF Eira, J Lopes, AT Malheiro, AR Sousa, V Luoma, A Avila, RL Wanders, RJ Just, WW Kirschner, DA Sousa, MM Brites, P |
dc.subject.por.fl_str_mv |
Animals Cell Differentiation/physiology Chondrodysplasia Punctata Rhizomelic/etiology Chondrodysplasia Punctata Rhizomelic/pathology Chondrodysplasia Punctata Rhizomelic/physiopathology Female Glycogen Synthase Kinase 3/antagonists & inhibitors Glycogen Synthase Kinase 3/metabolism Glycogen Synthase Kinase 3 beta Humans Male Mice Mice Knockout Mice Neurologic Mutants Models Neurological Myelin Basic Protein/metabolism Myelin Sheath/physiology Nerve Regeneration Peripheral Nervous System/cytology Peripheral Nervous System/physiology Peroxisomal Targeting Signal 2 Receptor Plasmalogens/physiology Proto-Oncogene Proteins c-akt/metabolism Receptors, Cytoplasmic and Nuclear/deficiency Receptors, Cytoplasmic and Nuclear/genetics Schwann Cells/cytology Schwann Cells/physiology Signal Transduction |
topic |
Animals Cell Differentiation/physiology Chondrodysplasia Punctata Rhizomelic/etiology Chondrodysplasia Punctata Rhizomelic/pathology Chondrodysplasia Punctata Rhizomelic/physiopathology Female Glycogen Synthase Kinase 3/antagonists & inhibitors Glycogen Synthase Kinase 3/metabolism Glycogen Synthase Kinase 3 beta Humans Male Mice Mice Knockout Mice Neurologic Mutants Models Neurological Myelin Basic Protein/metabolism Myelin Sheath/physiology Nerve Regeneration Peripheral Nervous System/cytology Peripheral Nervous System/physiology Peroxisomal Targeting Signal 2 Receptor Plasmalogens/physiology Proto-Oncogene Proteins c-akt/metabolism Receptors, Cytoplasmic and Nuclear/deficiency Receptors, Cytoplasmic and Nuclear/genetics Schwann Cells/cytology Schwann Cells/physiology Signal Transduction |
description |
Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014 2014-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10216/110350 |
url |
http://hdl.handle.net/10216/110350 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
0021-9738 10.1172/JCI72063 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Society for Clinical Investigation |
publisher.none.fl_str_mv |
American Society for Clinical Investigation |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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