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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bromodeoxyuridine
  • Cell Cycle / physiology
  • Cell Movement / physiology
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Choristoma / genetics*
  • Classical Lissencephalies and Subcortical Band Heterotopias
  • Doublecortin Protein
  • Electroporation
  • Humans
  • Immunohistochemistry
  • Intracranial Arteriovenous Malformations / pathology
  • Introns / genetics
  • Mice
  • Microscopy, Confocal
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / physiology*
  • Microtubules / physiology
  • Mitosis / physiology
  • Molecular Sequence Data
  • Mutation / physiology*
  • Neural Stem Cells / physiology*
  • Retroelements / physiology
  • Spindle Apparatus / physiology


  • Dcx protein, mouse
  • Doublecortin Protein
  • Eml1 protein, human
  • Eml1 protein, mouse
  • Microtubule-Associated Proteins
  • Retroelements
  • Bromodeoxyuridine

Associated data

  • GENBANK/KJ734704
  • GENBANK/KJ734705
  • GENBANK/KJ734706
  • GEO/GSE56907