{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:53:41Z","timestamp":1790261621001,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,10,27]],"date-time":"2015-10-27T00:00:00Z","timestamp":1445904000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08NS083710"],"award-info":[{"award-number":["K08NS083710"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01 NS078289"],"award-info":[{"award-number":["1R01 NS078289"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001771","name":"Tuberous Sclerosis Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001771","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>While abnormalities in myelin in tuberous sclerosis complex (<jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content>) have been known for some time, recent imaging\u2010based data suggest myelin abnormalities may be independent of the pathognomonic cortical lesions (\u201ctubers\u201d). Multiple mouse models of <jats:styled-content style=\"fixed-case\">TSC<\/jats:styled-content> exhibit myelination deficits, though the cell types responsible and the mechanisms underlying the myelin abnormalities remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To determine the role of alterations in <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling in myelination, we generated a conditional knockout (<jats:styled-content style=\"fixed-case\">CKO<\/jats:styled-content>) mouse model using Cre\u2010recombinase and the <jats:italic>Olig2<\/jats:italic> promoter to inactivate the <jats:italic>Tsc2<\/jats:italic> gene in oligodendrocyte precursor cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Characterization of myelin and myelin constituent proteins demonstrated a marked hypomyelination phenotype. Diffusion\u2010based magnetic resonance imaging studies were likewise consistent with hypomyelination. Hypomyelination was due in part to decreased myelinated axon density and myelin thickness as well as decreased oligodendrocyte numbers. Coincident with hypomyelination, an extensive gliosis was seen in both the cortex and white matter tracks, suggesting alterations in cell fate due to changes in <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> activity in oligodendrocyte precursors. Despite a high\u2010frequency appendicular tremor and altered gait in <jats:styled-content style=\"fixed-case\">CKO<\/jats:styled-content> mice, no significant changes in activity, vocalizations, or anxiety\u2010like phenotypes were seen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings support a known role of <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling in regulation of myelination and demonstrate that increased <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 activity early in development within oligodendrocytes results in hypomyelination and not hypermyelination. Our data further support a dissociation between decreased Akt activity and increased <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 activity toward hypomyelination. Thus, therapies promoting activation of Akt\u2010dependent pathways while reducing <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 activity may prove beneficial in treatment of human disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.254","type":"journal-article","created":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T07:44:09Z","timestamp":1446018249000},"page":"1041-1054","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Hypomyelination following deletion of <i>Tsc2<\/i> in oligodendrocyte precursors"],"prefix":"10.1002","volume":"2","author":[{"given":"Robert P.","family":"Carson","sequence":"first","affiliation":[{"name":"Department of Pediatrics Vanderbilt University Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel D.","family":"Kelm","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Vanderbilt 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