Cited by 261Neurogenesis and neuroplasticity mechanismsFetal and Pediatric Neurological DisordersDevelopmental Biology and Gene Regulation

An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome

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Iefremova, Vira, Manikakis, George, Krefft, Olivia, Jabali, Ammar, Weynans, Kevin, Wilkens, Ruven, Marsoner, Fabio, Brändl, Björn +3 more·2017·Cell Reports

Abstract

Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3ε) and leads to malformations during cortical development. Here, we used patient-specific forebrain-type organoids to investigate pathological changes associated with MDS. Patient-derived organoids are significantly reduced in size, a change accompanied by a switch from symmetric to asymmetric cell division of ventricular zone radial glia cells (vRGCs). Alterations in microtubule network organization in vRGCs and a disruption of cortical niche architecture, including altered expression of cell adhesion molecules, are also observed. These phenotypic changes lead to a non-cell-autonomous disturbance of the N-cadherin/β-catenin signaling axis. Reinstalling active β-catenin signaling rescues division modes and ameliorates growth defects. Our data define the role of LIS1 and 14.3.3ε in maintaining the cortical niche and highlight the utility of organoid-based systems for modeling complex cell-cell interactions in vitro.

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Crossref · 10.1016/j.celrep.2017.03.047

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  • A second report observed altered division mode of radial glial cells in Miller-Dieker syndrome organoids and identified non-cell-autonomous WNT signalling defects as an underlying mechanism.

    “A second report also observed changes in the division mode of radial glial cells in MDS organoids and identified non-cell-autonomous defects in WNT signalling as an underlying mechanism67.”

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Authors
Iefremova, V., Manikakis, G., Krefft, O., Jabali, A., Weynans, K., Wilkens, R., Marsoner, F., Brändl, B., Müller, F.-J., Koch, P., & Ladewig, J.
Affiliations
  • University of Bonn (DE)
  • University Hospital Schleswig-Holstein (DE)
Corresponding author
  • Koch, Philipp
  • Ladewig, Julia
Venue
Cell Reports
Publisher
Elsevier BV
Published
2017-04
Volume
19
Issue
1
Pages
50-59
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2604829166
Cited by
261
References
31
Citations by year
2026: 10 · 2025: 20 · 2024: 20 · 2023: 20 · 2022: 44 · 2021: 38 · 2020: 48 · 2019: 30 · 2018: 26 · 2017: 5
FWCI
12.64
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Deutsche Forschungsgemeinschaft (MU 3231/3-1)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Miller-Dieker syndrome, cortical development, organoids, LIS1, 14-3-3ε, YWHAE, Wnt signaling, β-catenin, N-cadherin, radial glia, asymmetric cell division, microtubule cytoskeleton, adhesion molecules, patient-derived organoids
MeSH terms
Cell Communication, Cell Division, Cerebral Cortex, Chromosome Deletion, Chromosomes, Human, Pair 17, Heterozygote, Humans, Microtubule-Associated Proteins, Models, Biological, Organoids, Cadherins, Gene Expression, Tissue Engineering, 1-Alkyl-2-acetylglycerophosphocholine Esterase, 14-3-3 Proteins, beta Catenin, Classical Lissencephalies and Subcortical Band Heterotopias, Stem Cell Niche, Wnt Signaling Pathway, Ependymoglial Cells

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