Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization

Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation becau...

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Autores: Cahana, Aviv, Escámez, Teresa, Nowakowski, Richard S., Hayes, Nancy L., Giacobini, MaiBritt, Holst, Alexander von, Shmueli, Orit, Sapir, Tamar, McConnell, Susan K., Wurst, Wolfgang, Martínez, Salvador, Reiner, Orly
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2001
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/338273
Acceso en línea:http://hdl.handle.net/10261/338273
Access Level:acceso abierto
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spelling Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerizationCahana, AvivEscámez, TeresaNowakowski, Richard S.Hayes, Nancy L.Giacobini, MaiBrittHolst, Alexander vonShmueli, OritSapir, TamarMcConnell, Susan K.Wurst, WolfgangMartínez, SalvadorReiner, OrlyLissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.This work was supported in part by the Fritz Thyssen Stiftung Foundation, Binational Science Foundation Grant No. 97–00014 (to O.R.), a grant from the Seneca Foundation of Murcia community, 708/CV/99 (to S.M.), a grant from the European Community, EC PL-960146 (to O.R., S.M., and W.W.), Human Frontier Science Program Organization Grant No. RG283199 9 (to O.R. and S.K.M.), and Volkswagen Stiftung (to O.R. and W.W.). O.R. is an Incumbent of the Aser Rothstein Career Development Chair in Genetic Diseases (Weizmann Institute).Peer reviewedNational Academy of Sciences (U.S.)Fritz Thyssen FoundationUnited States-Israel Binational Science FoundationFundación SénecaEuropean CommissionHuman Frontier Science ProgramVolkswagen FoundationWeizmann Institute of ScienceConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232001info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/338273reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.1073/pnas.101122598https://doi.org/10.1073/pnas.101122598Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3382732026-05-22T06:33:51Z
dc.title.none.fl_str_mv Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
title Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
spellingShingle Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
Cahana, Aviv
title_short Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
title_full Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
title_fullStr Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
title_full_unstemmed Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
title_sort Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization
dc.creator.none.fl_str_mv Cahana, Aviv
Escámez, Teresa
Nowakowski, Richard S.
Hayes, Nancy L.
Giacobini, MaiBritt
Holst, Alexander von
Shmueli, Orit
Sapir, Tamar
McConnell, Susan K.
Wurst, Wolfgang
Martínez, Salvador
Reiner, Orly
author Cahana, Aviv
author_facet Cahana, Aviv
Escámez, Teresa
Nowakowski, Richard S.
Hayes, Nancy L.
Giacobini, MaiBritt
Holst, Alexander von
Shmueli, Orit
Sapir, Tamar
McConnell, Susan K.
Wurst, Wolfgang
Martínez, Salvador
Reiner, Orly
author_role author
author2 Escámez, Teresa
Nowakowski, Richard S.
Hayes, Nancy L.
Giacobini, MaiBritt
Holst, Alexander von
Shmueli, Orit
Sapir, Tamar
McConnell, Susan K.
Wurst, Wolfgang
Martínez, Salvador
Reiner, Orly
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fritz Thyssen Foundation
United States-Israel Binational Science Foundation
Fundación Séneca
European Commission
Human Frontier Science Program
Volkswagen Foundation
Weizmann Institute of Science
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Lissencephaly is a severe brain malformation in humans. To study the function of the gene mutated in lissencephaly (LIS1), we deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimics a mutation described in one lissencephaly patient with a milder phenotype. Homozygotes are early lethal, although heterozygotes are viable and fertile. Most strikingly, the morphology of cortical neurons and radial glia is aberrant in the developing cortex, and the neurons migrate more slowly. This is the first demonstration, to our knowledge, of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalomocortical innervation are also abnormal. Biochemically, the mutant protein is not capable of dimerization, and enzymatic activity is elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of PAF-AH. This mutation allows us to determine a hierarchy of functions that are sensitive to LIS1 dosage, thus promoting our understanding of the role of LIS1 in the developing cortex.
publishDate 2001
dc.date.none.fl_str_mv 2001
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/338273
url http://hdl.handle.net/10261/338273
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI 10.1073/pnas.101122598
https://doi.org/10.1073/pnas.101122598
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences (U.S.)
publisher.none.fl_str_mv National Academy of Sciences (U.S.)
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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