ArticleDevelopmental neurobiology2021
STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation.
Article in Developmental neurobiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 2 of them syntheses that pooled it.
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Who cites it
27 citing papers in PubMed, 2 syntheses or guidelines pooled it, 37 citations in OpenAlex.
- Mapping the Cerebral Organoid Landscape: A Systematic Review of Preclinical 3D Models in Neuroscience.Advanced healthcare materials · 2026Pooled it
- Brain volumes in genetic syndromes associated with mTOR dysregulation: a systematic review and meta-analysis.Molecular psychiatry · 2025Pooled it
- Augmenting and Assaying Nav1.1 Protein Quantity for Dravet Syndrome Therapy.Annals of clinical and translational neurology · 2026Article
- Delayed forebrain excitatory and inhibitory neurogenesis in STRADA-related megalencephaly via mTOR hyperactivity.Stem cell reports · 2026Article
- Mechanistic Target of Rapamycin and Megalencephaly: Novel Research Strategies for Therapeutic Discovery.Epilepsy currents · 2026Article
- Dual developmental effects of ARX poly-alanine mutations on human cortical excitatory and inhibitory neurons.Cell reports · 2026Article
- Cryopreservation of human cortical organoids using vitrification.Frontiers in molecular neuroscience · 2026Article
- Pluripotent stem cells-based neural organoids for modelling human brain development and diseases.Cell & bioscience · 2025Review
- Organoids in Genetic Disorders: from Disease Modeling to Translational Applications.Stem cell reviews and reports · 2025Review
- mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.Orphanet journal of rare diseases · 2025Review
- Modelling human brain development and disease with organoids.Nature reviews. Molecular cell biology · 2025Review
- Review
- Article
- Brain organoids: a new paradigm for studying human neuropsychiatric disorders.Frontiers in neuroscience · 2025Review
- Using cortical organoids to understand the pathogenesis of malformations of cortical development.Frontiers in neuroscience · 2024Review
- Deriving early single-rosette brain organoids from human pluripotent stem cells.Stem cell reports · 2023Article
- Advances and Applications of Brain Organoids.Neuroscience bulletin · 2023Review
- The generation and properties of human cortical organoids as a disease model for malformations of cortical development.Neural regeneration research · 2023Review
- Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy.Brain : a journal of neurology · 2023Review
- A human liver organoid screening platform for DILI risk prediction.Journal of hepatology · 2023Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Genetic diseases involving overactivation of the mechanistic target of rapamycin (mTOR) pathway, so-called "mTORopathies," often manifest with malformations of cortical development (MCDs), epilepsy, and cognitive impairment. How mTOR pathway hyperactivation results in abnormal human cortical development is poorly understood. To study the effect of mTOR hyperactivity on early stages of cortical development, we focused on Pretzel Syndrome (polyhydramnios, megalencephaly, symptomatic epilepsy; PMSE syndrome), a rare mTORopathy caused by homozygous germline mutations in the STRADA gene. We developed a human cortical organoid (hCO) model of PMSE and examined morphology and size for the first 2 weeks of organoid growth, and cell type composition at weeks 2, 8, and 12 of differentiation. In the second week, PMSE hCOs enlarged more rapidly than controls and displayed an abnormal Wnt pathway-dependent increase in neural rosette structures. PMSE hCOs also exhibited delayed neurogenesis, decreased subventricular zone progenitors, increased proliferation and cell death, and an abnormal architecture of primary cilia. At week 8, PMSE hCOs had fewer deep layer neurons. By week 12, neurogenesis recovered in PMSE organoids, but they displayed increased outer radial glia, a cell type thought to contribute to the expansion of the human cerebral cortex. Together, these findings suggest that megalencephaly in PMSE arises from the expansion of neural stem cells in early corticogenesis and potentially also from increased outer radial glial at later gestational stages. The delayed neuronal differentiation in PMSE organoids demonstrates the important role the mTOR pathway plays in the maintenance and expansion of the stem cell pool.
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Registered trials
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