Related Experiment Video
Updated: Oct 18, 2025
In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects
Szilvia Galgoczi1, Albert Ruzo1, Christian Markopoulos1
1Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA.
Insights
Huntington's disease (HD) CAG expansion disrupts early human embryo development by affecting cell signaling and polarization. This reveals a critical developmental window for HD onset within the first two weeks of embryogenesis.
Area of Science:
- Developmental Biology
- Genetics
- Neuroscience
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder.
- HD is caused by CAG repeat expansion in the huntingtin gene (HTT).
- HD has a developmental component, but the earliest embryonic defects are unknown.
Purpose of the Study:
- To investigate the impact of HTT-CAG expansion on early human embryogenesis.
- To identify the earliest developmental window affected by HD.
- To model HD-related embryonic defects using human embryonic stem cells (hESCs).
Main Methods:
- Utilized a synthetic model of human gastrulation derived from hESCs.
- Created 2D gastruloids to model early human development.
- Analyzed CAG length-dependent phenotypic signatures and TGFβ signaling dynamics.
Main Results:
- Observed a CAG length-dependent reduction in ectodermal compartment extension.
- Identified enhanced activin signaling associated with ectodermal defects.
- Demonstrated that HTT-CAG expansion perturbs spatial restriction of TGFβ signaling, not cell-autonomously.
- Found defects in apicobasal polarization leading to ectopic TGFβ receptor localization.
Conclusions:
- HTT-CAG expansion causes embryonic defects via disrupted TGFβ signaling and cell polarization.
- The earliest prodromal phase of HD can occur within the first two weeks of human development.
- 2D gastruloids are a valuable model for studying early HD developmental effects.
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.
Related Concept Videos
02:33Hedgehog Signaling Pathway
01:56Gastrulation