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

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

Author information

1
INSERM U 1270, Paris, France; Sorbonne University, UMR-S 1270, 75005 Paris, France; Institut du Fer à Moulin, Paris, France.
2
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; HITBR Hector Institute for Translational Brain Research gGmbH, Mannheim, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, Paris, France.
4
Laboratory of Genetics and Development of the Cerebral Cortex, INSERM UMR1163 Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
5
Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, 91057 Evry, France.
6
Department of Clinical Genetics, Erasmus MC University Medical Center, 3015CN Rotterdam, the Netherlands.
7
Laboratory of Genetics and Development of the Cerebral Cortex, INSERM UMR1163 Imagine Institute, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France; Pediatric Neurology APHP-Necker Enfants Malades University Hospital, Paris, France; Centre de Référence, Déficiences Intellectuelles de Causes Rares, APHP-Necker Enfants Malades University Hospital, Paris, France.
8
INSERM U 1270, Paris, France; Sorbonne University, UMR-S 1270, 75005 Paris, France; Institut du Fer à Moulin, Paris, France. Electronic address: fiona.francis@inserm.fr.

Abstract

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

PMID:
31390572
DOI:
10.1016/j.celrep.2019.06.096
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