{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T21:22:44Z","timestamp":1791062564537,"version":"4.1.0"},"reference-count":62,"publisher":"National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,11,8]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) is a multiorgan genetic disease in which brain involvement causes epilepsy, intellectual disability, and autism. The hallmark pathological finding in TSC is the cerebral cortical tuber and its unique constituent, giant cells. However, an animal model that replicates giant cells has not yet been described. Here, we report that mosaic induction of\n                    <jats:italic>Tsc1<\/jats:italic>\n                    loss in neural progenitor cells in\n                    <jats:italic>\n                      Tsc1\n                      <jats:sup>cc<\/jats:sup>\n                      Nestin-rtTA\n                    <\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    <jats:italic>TetOp-cre<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    embryos by doxycycline leads to multiple neurological symptoms, including severe epilepsy and premature death. Strikingly,\n                    <jats:italic>Tsc1<\/jats:italic>\n                    -null neural progenitor cells develop into highly enlarged giant cells with enlarged vacuoles. We found that the vacuolated giant cells had multiple signs of organelle dysfunction, including markedly increased mitochondria, aberrant lysosomes, and elevated cellular stress. We found similar vacuolated giant cells in human tuber specimens. Postnatal rapamycin treatment completely reversed these phenotypes and rescued the mutants from epilepsy and premature death, despite prenatal onset of\n                    <jats:italic>Tsc1<\/jats:italic>\n                    loss and mTOR complex 1 activation in the developing brain. This TSC brain model provides insights into the pathogenesis and organelle dysfunction of giant cells, as well as epilepsy control in patients with TSC.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1106454108","type":"journal-article","created":{"date-parts":[[2011,10,25]],"date-time":"2011-10-25T01:52:20Z","timestamp":1319507540000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":167,"title":["Regulable neural progenitor-specific\n                    <i>Tsc1<\/i>\n                    loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex"],"prefix":"10.1073","volume":"108","author":[{"given":"June","family":"Goto","sequence":"first","affiliation":[{"name":"Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia M.","family":"Talos","sequence":"additional","affiliation":[{"name":"The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, and Program in Neurobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Klein","sequence":"additional","affiliation":[{"name":"The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, and Program in Neurobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Qin","sequence":"additional","affiliation":[{"name":"Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yvonne I.","family":"Chekaluk","sequence":"additional","affiliation":[{"name":"Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Anderl","sequence":"additional","affiliation":[{"name":"Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izabela A.","family":"Malinowska","sequence":"additional","affiliation":[{"name":"Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Di Nardo","sequence":"additional","affiliation":[{"name":"The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, and Program in Neurobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick T.","family":"Bronson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry V.","family":"Vinters","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Laboratory Medicine and Neurology, University of California Los Angeles Medical Center, Los Angeles, CA 90095; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven G.","family":"Kernie","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9133"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances E.","family":"Jensen","sequence":"additional","affiliation":[{"name":"The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, and Program in Neurobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Sahin","sequence":"additional","affiliation":[{"name":"The F. M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, and Program in Neurobiology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kwiatkowski","sequence":"additional","affiliation":[{"name":"Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,10,24]]},"reference":[{"key":"e_1_1_2_17_11_1_2","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1002\/9783527630073","volume-title":"Tuberous Sclerosis Complex","author":"Kwiatkowski DJ","year":"2010","unstructured":"DJ Kwiatkowski, EA Thiele, VH Whittemore Tuberous Sclerosis Complex (Wiley\u2013VCH, Weinheim, Germany), pp. 409 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