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Nat Neurosci. 2014 Jul;17(7):923-33. doi: 10.1038/nn.3729. Epub 2014 May 25.

Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human.

Author information

1
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].
2
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].
3
1] Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland. [2].
4
Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernández, Alicante, Spain.
5
Inserm U1016, Université René Descartes, Institut Cochin, Paris, France.
6
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
7
Hopital Necker Enfants Malades, Pediatric Neurology, Assistance Publique Hôpitaux de Paris, Université Paris Descartes, Paris, France.
8
Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Génomique, Centre National de Génotypage, 91057 Evry, France.
9
Service de Neuropédiatrie, Centre Hospitalier Universitaire Amiens-Nord, Amiens, France.
10
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.
11
1] Sorbonne Université, Université Pierre et Marie Curie, Paris, France. [2] Laboratoire de Biologie du Développement, CNRS UMR 7622, Paris, France.
12
Plateforme post-génomique de la Pitié-Salpêtrière, Faculty of Medicine, Paris, France.
13
Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.

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.

PMID:
24859200
DOI:
10.1038/nn.3729
[Indexed for MEDLINE]
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