ArticleDevelopment (Cambridge, England)2021
Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects.
Article in Development (Cambridge, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 23 citations in OpenAlex.
- Synthetic embryos: current progress, application and challenges.Reproductive biology and endocrinology : RB&E · 2026Review
- Targeted antisense oligonucleotide treatment rescues developmental alterations in spinal muscular atrophy organoids.Nature communications · 2025Article
- Stem cell-based human embryo models: current knowledge and open questions.Stem cell research & therapy · 2025Review
- Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics.Neuron · 2025Article
- Intersecting impact of CAG repeat and huntingtin knockout in stem cell-derived cortical neurons.Neurobiology of disease · 2025Article
- Development of large-scale gastruloid array to identify aberrant developmental phenotypes.APL bioengineering · 2025Article
- Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease.Neurobiology of disease · 2025Article
- Quantitative determination of the spatial distribution of components in single cells with CellDetail.Nature communications · 2024Article
- Exploring potential developmental origins of common neurodegenerative disorders.Biochemical Society transactions · 2024Review
- Review
- The brain on time: links between development and neurodegeneration.Development (Cambridge, England) · 2023Article
- Article
- Role of YAP in early ectodermal specification and a Huntington's Disease model of human neurulation.eLife · 2022Article
- YAP1 regulates the self-organized fate patterning of hESC-derived gastruloids.Stem cell reports · 2022Article
- Quantitative developmental biology in vitro using micropatterning.Development (Cambridge, England) · 2021Review
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG repeats in the huntingtin gene (HTT). Although HD has been shown to have a developmental component, how early during human embryogenesis the HTT-CAG expansion can cause embryonic defects remains unknown. Here, we demonstrate a specific and highly reproducible CAG length-dependent phenotypic signature in a synthetic model for human gastrulation derived from human embryonic stem cells (hESCs). Specifically, we observed a reduction in the extension of the ectodermal compartment that is associated with enhanced activin signaling. Surprisingly, rather than a cell-autonomous effect, tracking the dynamics of TGFβ signaling demonstrated that HTT-CAG expansion perturbs the spatial restriction of activin response. This is due to defects in the apicobasal polarization in the context of the polarized epithelium of the 2D gastruloid, leading to ectopic subcellular localization of TGFβ receptors. This work refines the earliest developmental window for the prodromal phase of HD to the first 2 weeks of human development, as modeled by our 2D gastruloids.
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