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Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects

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Item Type:Article
Title:Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects
Creators Name:Galgoczi, S. and Ruzo, A. and Markopoulos, C. and Yoney, A. and Phan-Everson, T. and Li, S. and Haremaki, T. and Metzger, J.J. and Etoc, F. and Brivanlou, A.H.
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.
Keywords:Huntington's Disease, Human Embryonic Stem Cells, 2D Gastruloids, TGFβ Signaling, Epithelial Polarity, Animals, Mice
Publisher:Company of Biologists
Page Range:dev199513
Date:October 2021
Official Publication:https://doi.org/10.1242/dev.199513
PubMed:View item in PubMed

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