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Neither its pathogenic mechanisms nor the normal functions of HTT are well understood. To model HD in humans, we engineered a genetic allelic series of isogenic human embryonic stem cell (hESC) lines with graded increases in CAG repeat length. Neural differentiation of these lines unveiled a novel developmental HD phenotype: the appearance of giant multinucleated telencephalic neurons at an abundance directly proportional to CAG repeat length, generated by a chromosomal instability and failed cytokinesis over multiple rounds of DNA replication. We conclude that disrupted neurogenesis during development is an important, unrecognized aspect of HD pathogenesis. To address the function of normal HTT protein we generated HTT+\/\u2212 and HTT\u2212\/\u2212 lines. Surprisingly, the same phenotype emerged in HTT\u2212\/\u2212 but not HTT+\/\u2212 lines. We conclude that HD is a developmental disorder characterized by chromosomal instability that impairs neurogenesis, and that HD represents a genetic dominant-negative loss of function, contrary to the prevalent gain-of-toxic-function hypothesis. The consequences of developmental alterations should be considered as a new target for HD therapies.<\/jats:p>","DOI":"10.1242\/dev.156844","type":"journal-article","created":{"date-parts":[[2018,1,30]],"date-time":"2018-01-30T01:10:34Z","timestamp":1517274634000},"source":"Crossref","is-referenced-by-count":68,"title":["Chromosomal instability during neurogenesis in Huntington's disease"],"prefix":"10.1242","volume":"145","author":[{"given":"Albert","family":"Ruzo","sequence":"first","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gist F.","family":"Croft","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob J.","family":"Metzger","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"},{"name":"The Rockefeller University 2 Center for Studies in Physics and Biology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szilvia","family":"Galgoczi","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren J.","family":"Gerber","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Hanbin","family":"Wang","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Fenner","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Tse","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Marks","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corbyn","family":"Nchako","sequence":"additional","affiliation":[{"name":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , 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":"The Rockefeller University 1 Laboratory of Stem Cell Biology and Molecular Embryology , , New York, NY 10065 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2018,1,29]]},"reference":[{"key":"2024061223462056400_DEV156844C1","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1093\/cercor\/bhq099","article-title":"Failed cytokinesis of neural progenitors in citron kinase-deficient rats leads to multiciliated neurons","volume":"21","author":"Anastas","year":"2011","journal-title":"Cereb. 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