title: Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.
abstract: Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.
authors.affiliation: 1] Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. [2] Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland. [3].
authors.forename: Michel
authors.initials: M
authors.lastname: Kielar
authors.affiliation: 1] Inserm UMR-S 839, F75005, Paris, France. [2] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [3] Institut du Fer à Moulin, Paris, France. [4].
authors.forename: Françoise Phan Dinh
authors.initials: FP
authors.lastname: Tuy
authors.affiliation: 1] Inserm UMR-S 839, F75005, Paris, France. [2] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [3] Institut du Fer à Moulin, Paris, France. [4].
authors.forename: Sara
authors.initials: S
authors.lastname: Bizzotto
authors.affiliation: 1] Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland. [2].
authors.forename: Cécile
authors.initials: C
authors.lastname: Lebrand
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernández, Alicante, Spain.
authors.forename: Camino
authors.initials: C
authors.lastname: de Juan Romero
authors.affiliation: Inserm U1016, Université René Descartes, Institut Cochin, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Oegema
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Mancini
authors.affiliation: Hopital Necker Enfants Malades, Pediatric Neurology, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.affiliation: Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Génomique, Centre National de Génotypage, 91057 Evry, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Olaso
authors.affiliation: Service de Neuropédiatrie, Centre Hospitalier Universitaire Amiens-Nord, Amiens, France.
authors.forename: Anne-Gaëlle
authors.initials: AG
authors.lastname: Le Moing
authors.affiliation: 1] Inserm UMR-S 839, F75005, Paris, France. [2] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [3] Institut du Fer à Moulin, Paris, France.
authors.forename: Katia
authors.initials: K
authors.lastname: Boutourlinsky
authors.affiliation: 1] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [2] Laboratoire de Biologie du Développement, CNRS UMR 7622, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Boucher
authors.affiliation: Plateforme post-génomique de la Pitié-Salpêtrière, Faculty of Medicine, Paris, France.
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.affiliation: Service de Neuropédiatrie, Centre Hospitalier Universitaire Amiens-Nord, Amiens, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Berquin
authors.affiliation: Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Génomique, Centre National de Génotypage, 91057 Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: 1] Inserm UMR-S 839, F75005, Paris, France. [2] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [3] Institut du Fer à Moulin, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Belvindrah
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernández, Alicante, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Borrell
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
authors.forename: Egbert
authors.initials: E
authors.lastname: Welker
authors.affiliation: Inserm U1016, Université René Descartes, Institut Cochin, Paris, France.
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.affiliation: 1] Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. [2] Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland. [3].
authors.forename: Alexandre
authors.initials: A
authors.lastname: Croquelois
authors.affiliation: 1] Inserm UMR-S 839, F75005, Paris, France. [2] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [3] Institut du Fer à Moulin, Paris, France. [4].
authors.forename: Fiona
authors.initials: F
authors.lastname: Francis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001973:Bromodeoxyuridine; D002453:Cell Cycle / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D002828:Choristoma / Q000235:genetics*; D054221:Classical Lissencephalies and Subcortical Band Heterotopias; D000089662:Doublecortin Protein; D018274:Electroporation; D006801:Humans; D007150:Immunohistochemistry; D002538:Intracranial Arteriovenous Malformations / Q000473:pathology; D007438:Introns / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000502:physiology*; D008870:Microtubules / Q000502:physiology; D008938:Mitosis / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D058953:Neural Stem Cells / Q000502:physiology*; D018626:Retroelements / Q000502:physiology; D008941:Spindle Apparatus / Q000502:physiology
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; C000590874:Eml1 protein, human; C000590875:Eml1 protein, mouse; D008869:Microtubule-Associated Proteins; D018626:Retroelements; D001973:Bromodeoxyuridine