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

• DOI: 10.1016/j.celrep.2019.06.096
• Publication Date: 2019-08-06T17:46:11Z
• Authors: Ana Uzquiano; Carmen Cifuentes-...; Ammar Jabali; Delfina M. Romero; Anne Houllier; Florent Dingli; Camille Maillard; Anne Boland; Jean-François Del...; Damarys Loew; Grazia M.S. Mancini; Nadia Bahi-Buisson; Julia Ladewig; Fiona Francis
• Keywords: Male; induced pluripotent stem cell; Adolescent; [SDV]Life Sciences [q-bio]; radial glia; EMC OR-01; Golgi Apparatus; Classical Lissencephalies and Subcortical Band Heterotopias; Mice; 03 medical and health sciences; ventricular zone; Pregnancy; Animals; Humans; cortical development; Cilia; Cells, Cultured; Adaptor Proteins, Signal Transducing; 0303 health sciences; cortical malformation; progenitor; HEK293 Cells; Golgi apparatus; Mutation; subcortical heterotopia; Female; Microtubule-Associated Proteins; primary cilium; microtubule

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.