TY  - JOUR
AU  - Zaidi, Donia
AU  - Chinnappa, Kaviya
AU  - Yigit, Berfu Nur
AU  - Viola, Valeria
AU  - Cifuentes-Diaz, Carmen
AU  - Jabali, Ammar
AU  - Uzquiano, Ana
AU  - Lemesre, Emilie
AU  - Perez, Franck
AU  - Ladewig, Julia
AU  - Ferent, Julien
AU  - Ozlu, Nurhan
AU  - Francis, Fiona
TI  - Forebrain Eml1 depletion reveals early centrosomal dysfunction causing subcortical heterotopia.
JO  - The journal of cell biology
VL  - 223
IS  - 12
SN  - 0021-9525
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DKFZ-2024-01917
SP  - e202310157
PY  - 2024
AB  - Subcortical heterotopia is a cortical malformation associated with epilepsy, intellectual disability, and an excessive number of cortical neurons in the white matter. Echinoderm microtubule-associated protein like 1 (EML1) mutations lead to subcortical heterotopia, associated with abnormal radial glia positioning in the cortical wall, prior to malformation onset. This perturbed distribution of proliferative cells is likely to be a critical event for heterotopia formation; however, the underlying mechanisms remain unexplained. This study aimed to decipher the early cellular alterations leading to abnormal radial glia. In a forebrain conditional Eml1 mutant model and human patient cells, primary cilia and centrosomes are altered. Microtubule dynamics and cell cycle kinetics are also abnormal in mouse mutant radial glia. By rescuing microtubule formation in Eml1 mutant embryonic brains, abnormal radial glia delamination and heterotopia volume were significantly reduced. Thus, our new model of subcortical heterotopia reveals the causal link between Eml1's function in microtubule regulation and cell position, both critical for correct cortical development.
KW  - Animals
KW  - Centrosome: metabolism
KW  - Humans
KW  - Microtubule-Associated Proteins: genetics
KW  - Microtubule-Associated Proteins: metabolism
KW  - Prosencephalon: metabolism
KW  - Prosencephalon: pathology
KW  - Prosencephalon: embryology
KW  - Microtubules: metabolism
KW  - Mice
KW  - Cilia: metabolism
KW  - Cilia: pathology
KW  - Mutation: genetics
KW  - Ependymoglial Cells: metabolism
KW  - Ependymoglial Cells: pathology
KW  - Cell Cycle: genetics
KW  - Microtubule-Associated Proteins (NLM Chemicals)
KW  - Eml1 protein, mouse (NLM Chemicals)
KW  - Eml1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39316454
DO  - DOI:10.1083/jcb.202310157
UR  - https://inrepo02.dkfz.de/record/293600
ER  -