Faculty of Biology and Medicine at University of Lausanne & Lausanne University Hospital
Published June 30, 2014 | Version v1
Journal article Open

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

Creators

  • 1. Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
  • 2. Inserm UMR-S 839, F75005, Paris, France. Sorbonne Université, Université Pierre et Marie Curie, Paris, France. Institut du Fer à Moulin, Paris, France.
  • 3. Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
  • 4. Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernández, Alicante, Spain.
  • 5. Department of Fundamental Neurosciences, University Lausanne, Lausanne, Switzerland.
  • 6. Inserm U1016, Université René Descartes, Institut Cochin, Paris, France.
  • 7. Department of Clinical Neuroscience, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. Department of Fundamental Neurosciences, University Lausanne, Lausanne, Switzerland.

Description

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 identifiedEml1, 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 EML1to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

Notes

These authors contributed equally to the work. Michel Kielar, Françoise Phan Dinh Tuy, Sara Bizzotto & Cécile Lebrand These authors jointly directed this work. Alexandre Croquelois & Fiona Francis Terms for reuse of archived manuscripts For NPG-published material that has been archived into academic repositories such as institutional repositories, PubMed Central and its mirror sites, where NPG holds copyright, or an exclusive license to publish, users may view, print, copy, download and text and data-mine the content, for the purposes of academic research, subject always to the full Conditions of use. Conditions of use Articles published by Nature Publishing Group (NPG) which are made available through academic repositories remain subject to copyright. Any reuse is subject to permission from NPG.

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