1. Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects
- Author
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Jakob J. Metzger, Christian Markopoulos, Szilvia Galgoczi, Ali H. Brivanlou, Anna Yoney, Fred Etoc, Tomomi Haremaki, Albert Ruzo, Tien Phan-Everson, and Shu Li
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,Huntingtin ,TGFβ signaling ,Human Development ,2D gastruloids ,Human Embryonic Stem Cells ,Stem Cells & Regeneration ,Context (language use) ,Germ layer ,Biology ,Cell Line ,Mice ,Huntington's disease ,Transforming Growth Factor beta ,mental disorders ,medicine ,Animals ,Humans ,Compartment (development) ,Human embryogenesis ,Cell Lineage ,Molecular Biology ,Cells, Cultured ,Huntingtin Protein ,Epithelial polarity ,Cell Polarity ,Epithelial Cells ,medicine.disease ,Embryonic stem cell ,Activins ,Cell biology ,nervous system diseases ,Gastrulation ,Trinucleotide Repeat Expansion ,Germ Layers ,Signal Transduction ,Developmental Biology - 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., Summary: 2D gastruloids of isogenic human embryonic stem cells modeling Huntington's Disease reveal that huntingtin CAG expansion perturbs the spatial restriction of the activin response in the context of the polarized epithelium.
- Published
- 2021