{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T07:35:46Z","timestamp":1776065746587,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2013,9,25]],"date-time":"2013-09-25T00:00:00Z","timestamp":1380067200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"crossref","award":["R01NS060804 (to M.J.G.)"],"award-info":[{"award-number":["R01NS060804 (to M.J.G.)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Comparative Neurology"],"published-print":{"date-parts":[[2013,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with variable expressivity. Heterozygous mutations in either of two genes,<jats:italic>TSC1<\/jats:italic>(hamartin) or<jats:italic>TSC2<\/jats:italic>(tuberin), are responsible for most cases. Hamartin and tuberin form a heterodimer that functions as a major cellular inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) kinase. Genotype\u2010phenotype studies suggest that<jats:italic>TSC2<\/jats:italic>mutations are associated with a more severe neurologic phenotype, although the biologic basis for the difference between<jats:italic>TSC1<\/jats:italic>\u2010 and<jats:italic>TSC2<\/jats:italic>\u2010based disease is unclear. Here we performed a study to compare and contrast the brain phenotypes of<jats:italic>Tsc1<\/jats:italic>and<jats:italic>Tsc2<\/jats:italic>single and double mutants. Using<jats:italic>Tsc1<\/jats:italic>and<jats:italic>Tsc2<\/jats:italic>floxed alleles and a radial glial transgenic Cre driver (FVB\u2010Tg(GFAP\u2010cre)25Mes\/J), we deleted<jats:italic>Tsc1<\/jats:italic>and\/or<jats:italic>Tsc2<\/jats:italic>in radial glial progenitor cells. Single and double mutants had remarkably similar phenotypes: early postnatal mortality, brain overgrowth, laminar disruption, astrogliosis, a paucity of oligodendroglia, and myelination defects. Double<jats:italic>Tsc1\/Tsc2<\/jats:italic>mutants died earlier than single mutants, and single mutants showed differences in the location of heterotopias and the organization of the hippocampal stratum pyramidale. The differences were not due to differential mTORC1 activation or feedback inhibition on Akt. These data provide further genetic evidence for individual hamartin and tuberin functions that may explain some of the genotype\u2013phenotype differences seen in the human disease. J. Comp. Neurol. 521:3817\u20133831, 2013. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/cne.23380","type":"journal-article","created":{"date-parts":[[2013,6,8]],"date-time":"2013-06-08T06:48:40Z","timestamp":1370674120000},"page":"3817-3831","source":"Crossref","is-referenced-by-count":25,"title":["Comparative analysis of<i>Tsc1<\/i>and<i>Tsc2<\/i>single and double radial glial cell mutants"],"prefix":"10.1002","volume":"521","author":[{"given":"Ulrike","family":"Mietzsch","sequence":"first","affiliation":[{"name":"Department of Pediatrics\/Neonatology Indiana School of Medicine Indianapolis Indiana 46202"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"James","family":"McKenna","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia 30322"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. Michelle","family":"Reith","sequence":"additional","affiliation":[{"name":"Program in Human and Molecular Genetics University of Texas Health Science Center at Houston Houston Texas 77030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon W.","family":"Way","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Chicago Chicago Illinois 60637"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Gambello","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia 30322"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,9,25]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1086\/302648"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e31803068c7"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02847"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.08.024"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/63.12.1236"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90618-Z"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738040190091301"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra055323"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1086\/316951"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00735-09"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738040190090401"},{"key":"e_1_2_8_13_1","doi-asserted-by":"crossref","first-page":"5926","DOI":"10.1523\/JNEUROSCI.0778-09.2009","article-title":"Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR\u2010dependent manner","volume":"29","author":"DiNardo A","year":"2009","journal-title":"J Neurosci"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13044-9"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.260794"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780195122107.001.0001","volume-title":"Tuberous sclerosis complex","author":"Gomez MR","year":"1999"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1106454108"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2011.02.001"},{"key":"e_1_2_8_19_1","first-page":"1639","article-title":"Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two\u2010hit model for the pathogenesis of tuberous sclerosis tumors","volume":"151","author":"Henske E","year":"1997","journal-title":"Am J Pathol"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0370217"},{"key":"e_1_2_8_21_1","doi-asserted-by":"crossref","first-page":"4101","DOI":"10.1128\/MCB.00289-08","article-title":"The TSC1\u2010TSC2 complex is required for proper activation of mTOR complex 2","volume":"28","author":"Huang J","year":"2008","journal-title":"Mol Cell Biol"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.12.2155"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1086\/302381"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2003.012757"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25893"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A0642"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00116-8"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5540-06.2007"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.209114"},{"key":"e_1_2_8_30_1","first-page":"4766","article-title":"Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles","volume":"58","author":"Plank T","year":"1998","journal-title":"Cancer Res"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10350"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00333-6"},{"key":"e_1_2_8_33_1","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1111\/j.1750-3639.2010.00416.x","article-title":"Analysis of TSC cortical tubers by deep sequencing ofr TSC1, TSC2 and KRAS demonstrates that small hit mutation in these genes are rare events","volume":"20","author":"Qin W","year":"2012","journal-title":"Brain Pathol"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0033291701004561"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2008.01.001"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201402"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2005.09.009"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0234-09.2009"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10283"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5327.805"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddp025"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1089\/rej.2009.1015"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026343"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq491"}],"container-title":["Journal of Comparative Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcne.23380","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cne.23380","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T01:10:23Z","timestamp":1715476223000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cne.23380"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,25]]},"references-count":43,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2013,11]]}},"alternative-id":["10.1002\/cne.23380"],"URL":"https:\/\/doi.org\/10.1002\/cne.23380","archive":["Portico"],"relation":{},"ISSN":["0021-9967","1096-9861"],"issn-type":[{"value":"0021-9967","type":"print"},{"value":"1096-9861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9,25]]}}}