Journal Article

DKFZ-2024-01917

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Forebrain Eml1 depletion reveals early centrosomal dysfunction causing subcortical heterotopia.

Zaidi, D. ; Chinnappa, K. ; Yigit, B. N. ; Viola, V. ; Cifuentes-Diaz, C. ; Jabali, A.DKFZ* ; Uzquiano, A. ; Lemesre, E. ; Perez, F. ; Ladewig, J.DKFZ* ; Ferent, J. ; Ozlu, N. ; Francis, F.

2024
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1083/jcb.202310157

Abstract: 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.

Keyword(s): Animals (MeSH) ; Centrosome: metabolism (MeSH) ; Humans (MeSH) ; Microtubule-Associated Proteins: genetics (MeSH) ; Microtubule-Associated Proteins: metabolism (MeSH) ; Prosencephalon: metabolism (MeSH) ; Prosencephalon: pathology (MeSH) ; Prosencephalon: embryology (MeSH) ; Microtubules: metabolism (MeSH) ; Mice (MeSH) ; Cilia: metabolism (MeSH) ; Cilia: pathology (MeSH) ; Mutation: genetics (MeSH) ; Ependymoglial Cells: metabolism (MeSH) ; Ependymoglial Cells: pathology (MeSH) ; Cell Cycle: genetics (MeSH) ; Microtubule-Associated Proteins ; Eml1 protein, mouse ; Eml1 protein, human

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Contributing Institute(s):

1. A340 NWG Engeneering von Zellidentitäten und Krankheitsmodellen (A340)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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