{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:11:15Z","timestamp":1781658675623,"version":"3.54.5"},"reference-count":46,"publisher":"The Company of Biologists","issue":"19","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"CHDI Foundation","award":["A-9423"],"award-info":[{"award-number":["A-9423"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>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 TGF\u03b2 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 TGF\u03b2 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.<\/jats:p>","DOI":"10.1242\/dev.199513","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T07:07:40Z","timestamp":1633417660000},"source":"Crossref","is-referenced-by-count":21,"title":["Huntingtin CAG expansion impairs germ layer patterning in synthetic human 2D gastruloids through polarity defects"],"prefix":"10.1242","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8248-3314","authenticated-orcid":false,"given":"Szilvia","family":"Galgoczi","sequence":"first","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Ruzo","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Markopoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4988-9237","authenticated-orcid":false,"given":"Anna","family":"Yoney","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"},{"name":"Laboratory of condensed matter physics, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tien","family":"Phan-Everson","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"},{"name":"Laboratory of condensed matter physics, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Haremaki","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob J.","family":"Metzger","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"},{"name":"Laboratory of condensed matter physics, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fred","family":"Etoc","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"},{"name":"Laboratory of condensed matter physics, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1761-280X","authenticated-orcid":false,"given":"Ali H.","family":"Brivanlou","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"2021101115591026300_DEV199513C1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1038\/nrm2618","article-title":"Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo","volume":"10","author":"Arnold","year":"2009","journal-title":"Nat. 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