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

• Published in: Cell reports (Cambridge) 2019-08, Vol.28 (6), p.1596-1611.e10
• Main Authors: Uzquiano, Ana, Cifuentes-Diaz, Carmen, Jabali, Ammar, Romero, Delfina M., Houllier, Anne, Dingli, Florent, Maillard, Camille, Boland, Anne, Deleuze, Jean-François, Loew, Damarys, Mancini, Grazia M.S., Bahi-Buisson, Nadia, Ladewig, Julia, Francis, Fiona
• Format: Article
• Language: English
• Subjects: cortical development; cortical malformation; Golgi apparatus; induced pluripotent stem cell; Life Sciences; microtubule; primary cilium; progenitor; radial glia; subcortical heterotopia; ventricular zone
• ISSN: 2211-1247; 2211-1247
• 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. [Display omitted] •Primary cilium formation is impaired in Eml1/EML1 mutant apical radial glia•EML1 interacts with RPGRIP1L, a primary cilium protein•RPGRIP1L shows gene variations in a patient with subcortical heterotopia•Altered Golgi apparatus in Eml1 mutant cells may perturb the Golgi-primary cilium axis Uzquiano et al. show that mutations in Eml1/EML1, found in mice and patients with subcortical heterotopia, impair primary cilia formation in apical progenitors. Perturbed anterograde trafficking from the Golgi apparatus seems likely to contribute to this ciliary phenotype. This work uncovers pathological mechanisms potentially triggering the formation of the heterotopia.