Mutations in the Heterotopia Gene Eml1/EML1 Severely Disrupt the Formation of Primary Cilia

Cell Rep. 2019 Aug 6;28(6):1596-1611.e10. doi: 10.1016/j.celrep.2019.06.096.


Apical radial glia (aRGs) are predominant progenitors during corticogenesis. Perturbing their function leads to cortical malformations, including subcortical heterotopia (SH), characterized by the presence of neurons below the cortex. EML1/Eml1 mutations lead to SH in patients, as well as to heterotopic cortex (HeCo) mutant mice. In HeCo mice, some aRGs are abnormally positioned away from the ventricular zone (VZ). Thus, unraveling EML1/Eml1 function will clarify mechanisms maintaining aRGs in the VZ. We pinpoint an unknown EML1/Eml1 function in primary cilium formation. In HeCo aRGs, cilia are shorter, less numerous, and often found aberrantly oriented within vesicles. Patient fibroblasts and human cortical progenitors show similar defects. EML1 interacts with RPGRIP1L, a ciliary protein, and RPGRIP1L mutations were revealed in a heterotopia patient. We also identify Golgi apparatus abnormalities in EML1/Eml1 mutant cells, potentially upstream of the cilia phenotype. We thus reveal primary cilia mechanisms impacting aRG dynamics in physiological and pathological conditions.

Keywords: Golgi apparatus; cortical development; cortical malformation; induced pluripotent stem cell; microtubule; primary cilium; progenitor; radial glia; subcortical heterotopia; ventricular zone.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adolescent
  • Animals
  • Cells, Cultured
  • Cilia / genetics*
  • Cilia / pathology
  • Classical Lissencephalies and Subcortical Band Heterotopias / genetics*
  • Classical Lissencephalies and Subcortical Band Heterotopias / pathology
  • Female
  • Golgi Apparatus / genetics
  • Golgi Apparatus / pathology
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Microtubule-Associated Proteins / genetics*
  • Mutation
  • Pregnancy


  • Adaptor Proteins, Signal Transducing
  • Eml1 protein, human
  • Microtubule-Associated Proteins
  • RPGRIP1L protein, human