Publication: Forebrain Eml1 depletion reveals early centrosomal dysfunction causing subcortical heterotopia
dc.contributor.coauthor | Zaidi,Donia | |
dc.contributor.coauthor | Chinnappa,Kaviya | |
dc.contributor.coauthor | Viola,Valeria | |
dc.contributor.coauthor | Cifuentes-Diaz,Carmen | |
dc.contributor.coauthor | Jabali,Ammar | |
dc.contributor.coauthor | Uzquiano,Ana | |
dc.contributor.coauthor | Lemesre,Emilie | |
dc.contributor.coauthor | Perez,Franck | |
dc.contributor.coauthor | Ladewig,Julia | |
dc.contributor.coauthor | Ferent,Julien | |
dc.contributor.coauthor | Francis,Fiona | |
dc.contributor.department | KUTTAM (Koç University Research Center for Translational Medicine) | |
dc.contributor.department | Graduate School of Sciences and Engineering | |
dc.contributor.department | School of Medicine | |
dc.contributor.kuauthor | Yiğit, Berfu Nur | |
dc.contributor.schoolcollegeinstitute | GRADUATE SCHOOL OF SCIENCES AND ENGINEERING | |
dc.contributor.schoolcollegeinstitute | Research Center | |
dc.contributor.schoolcollegeinstitute | SCHOOL OF MEDICINE | |
dc.date.accessioned | 2025-03-06T20:58:59Z | |
dc.date.issued | 2024 | |
dc.description.abstract | Mechanisms leading to abnormal distribution of neural progenitors during cortical development in the context of subcortical heterotopia associated with EML1 mutations remain unknown. Using a forebrain-specific mouse model and mutant human cells, this work innovatively demonstrates that by restoring microtubule function, abnormal progenitor distribution and heterotopic volume are significantly reduced. Subcortical heterotopia is a cortical malformation associated with epilepsy, intellectual disability, and an excessive number of cortical neurons in the white matter. Echinoderm microtubule-associated protein like 1 (EML1) mutations lead to subcortical heterotopia, associated with abnormal radial glia positioning in the cortical wall, prior to malformation onset. This perturbed distribution of proliferative cells is likely to be a critical event for heterotopia formation;however, the underlying mechanisms remain unexplained. This study aimed to decipher the early cellular alterations leading to abnormal radial glia. In a forebrain conditional Eml1 mutant model and human patient cells, primary cilia and centrosomes are altered. Microtubule dynamics and cell cycle kinetics are also abnormal in mouse mutant radial glia. By rescuing microtubule formation in Eml1 mutant embryonic brains, abnormal radial glia delamination and heterotopia volume were significantly reduced. Thus, our new model of subcortical heterotopia reveals the causal link between Eml1's function in microtubule regulation and cell position, both critical for correct cortical development. | |
dc.description.indexedby | WOS | |
dc.description.indexedby | PubMed | |
dc.description.publisherscope | International | |
dc.description.sponsoredbyTubitakEu | N/A | |
dc.description.sponsorship | We are grateful to Dr. A. Baffet, V. Marthiens, and members of the lab for comments and discussions. We thank Dominic Norris for the RUSH PKD2 construction and Gaelle Boncompain for aid with other RUSH constructs. We thank Anne Houllier for aid with western blots and lab members for support. We thank the IFM animal experimentation facility, and cellular and tissue imaging platforms at the Institut du Fer a Moulin, supported also by the Region Ile de France and the FRC Rotary. We also thank the TAAM (CDTA, Orleans) for aid with animal maintenance.This project was supported by the French Agence Nationale de la Recherche (ANR) under the frame of E-Rare-3, the ERA-Net for Research on Rare Diseases (ERARE18-049, to F. Francis and N. Ozlu), and the Fondation pour la recherche medicale (FRM,Equipe FRM 2020 awarded to F. Francis EQU202003010323).Further funding was obtained from the JTC 2015 Neuro-developmental Disorders affiliated with the ANR (for NEU-RON8-Full- 815-006 STEM-MCD, to F. Francis and J. Ladewig) and the Hector Stiftung II and the German research foundation project LA 2933/2-1 to J. Ladewig). F. Francis's group were also involved in the European Cooperation on Science and Technology (COST Action CA16118), Neuro MIG project. We also thank the French Rare Diseases foundation and the PHENOMIN-ICS, France for the original Eml1 mouse model generation, as well as Dr. M. Groszer for provision of the Emx1-Cre line and Dr. K.Jones for agreement to use this. Our salaries and lab were supported by Institut National de la Sante et de la Recherche Medicale and the Centre national de la recherche scientifique. D.Zaidi was supported by an FRM grant FDT202204015115 and Sorbonne University. K. Chinnappa was supported by a BourseValerie Chamaillard awarded by the Fondation de France afterranking by the French Foundation for Research on Epilepsy. V.Viola was supported by Sorbonne University. J. Ferent obtained funding from the ATIP-Avenir program. The ANR project Ri-bocortex helped support this project (ANR-22-CE16-0025-01). | |
dc.identifier.doi | 10.1083/jcb.202310157 | |
dc.identifier.eissn | 1540-8140 | |
dc.identifier.grantno | French Agence Nationale de la Recherche (ANR) [ERARE18-049];Fondation pour la recherche medicale (FRM) [EQU202003010323];JTC;ANR [NEU-RON8-Full- 815-006 STEM-MCD, ANR-22-CE16-0025-01];Hector Stiftung II;German research foundation [LA 2933/2-1];COST Action [CA16118];Institut National de la Sante et de la Recherche Medicale;Centre national de la recherche scientifique;FRM [FDT202204015115];Sorbonne University;BourseValerie Chamaillard - Fondation de France afterranking by the French Foundation;ATIP-Avenir program | |
dc.identifier.issn | 0021-9525 | |
dc.identifier.issue | 12 | |
dc.identifier.quartile | Q1 | |
dc.identifier.uri | https://doi.org/10.1083/jcb.202310157 | |
dc.identifier.uri | https://hdl.handle.net/20.500.14288/27600 | |
dc.identifier.volume | 223 | |
dc.identifier.wos | 1319254700001 | |
dc.keywords | Subcortical heterotopia | |
dc.keywords | Cortical malformation | |
dc.keywords | Epilepsy | |
dc.language.iso | eng | |
dc.publisher | Rockefeller University Press | |
dc.relation.ispartof | Journal of Cell Biology | |
dc.subject | Cell biology | |
dc.title | Forebrain Eml1 depletion reveals early centrosomal dysfunction causing subcortical heterotopia | |
dc.type | Journal Article | |
dspace.entity.type | Publication | |
local.contributor.kuauthor | Yiğit, Berfu Nur | |
local.contributor.kuauthor | Özlü, Nurhan | |
local.publication.orgunit1 | GRADUATE SCHOOL OF SCIENCES AND ENGINEERING | |
local.publication.orgunit1 | SCHOOL OF MEDICINE | |
local.publication.orgunit1 | Research Center | |
local.publication.orgunit2 | KUTTAM (Koç University Research Center for Translational Medicine) | |
local.publication.orgunit2 | School of Medicine | |
local.publication.orgunit2 | Graduate School of Sciences and Engineering | |
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