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XB-ART-58540
Development October 1, 2021; 148 (19):
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Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects.

Galgoczi S , Ruzo A , Markopoulos C , Yoney A , Phan-Everson T , Li S , Haremaki T , Metzger JJ , Etoc F , Brivanlou AH .


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.

PubMed ID: 34608934
PMC ID: PMC8513611
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: acvr2b bmp4 bmpr2 eomes gata3 h2bc21 htt nodal nog smad1 smad2 sox17b.1 sox2 tbxt wnt3a
GO keywords: gastrulation

Disease Ontology terms: Huntington's disease
OMIMs: HUNTINGTON DISEASE; HD

Article Images: [+] show captions