An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome
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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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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.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [67]
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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
- gold
- doi.org
- Licence
- 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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