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

Cell Reports
Ana UzquianoFiona Francis

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.

Citations

Nov 12, 2019·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Renske OegemaMaarten H Lequin
Mar 30, 2020·Scientific Reports·G B CollinP M Nishina
Jan 1, 2021·Neurobiology of Disease·Abraham Andreu-CerveraSylvie Schneider-Maunoury
Aug 1, 2020·Seminars in Cell & Developmental Biology·Sarah K Suciu, Tamara Caspary
Jan 23, 2021·Science·Esther KlinglerSilvia Cappello
Nov 13, 2020·Frontiers in Cell and Developmental Biology·Julien FerentFiona Francis
Feb 20, 2021·Frontiers in Cell and Developmental Biology·Kerstin Hasenpusch-Theil, Thomas Theil
Oct 24, 2020·Current Opinion in Neurobiology·Fiona Francis, Silvia Cappello

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