{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:49:59Z","timestamp":1772603399239,"version":"3.50.1"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T00:00:00Z","timestamp":1662336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations that inactivate <jats:italic>TSC1<\/jats:italic> or <jats:italic>TSC2<\/jats:italic>. Hamartin and tuberin are encoded by <jats:italic>TSC1<\/jats:italic> and <jats:italic>TSC2<\/jats:italic> which form a GTPase activating protein heteromer that inhibits the Rheb GTPase from activating a growth promoting protein kinase called mammalian target of rapamycin (mTOR). Growths and lesions occur in the ventricular-subventricular zone (V-SVZ), cortex, olfactory tract, and olfactory bulbs (OB) in TSC. A leading hypothesis is that mutations in inhibitory neural progenitor cells cause brain growths in TSC. OB granule cells (GCs) are GABAergic inhibitory neurons that are generated through infancy by inhibitory progenitor cells along the V-SVZ. Removal of <jats:italic>Tsc1<\/jats:italic> from mouse OB GCs creates cellular phenotypes seen in TSC lesions. However, the role of <jats:italic>Tsc2<\/jats:italic> in OB GC maturation requires clarification. Here, it is demonstrated that conditional loss of <jats:italic>Tsc2<\/jats:italic> alters GC development. A mosaic model of TSC was created by performing neonatal CRE recombinase electroporation into inhibitory V-SVZ progenitors yielded clusters of ectopic cytomegalic neurons with hyperactive mTOR complex 1 (mTORC1) in homozygous <jats:italic>Tsc2<\/jats:italic> mutant but not heterozygous or wild type mice. Similarly, homozygous <jats:italic>Tsc2<\/jats:italic> mutant GC morphology was altered at postnatal days 30 and 60. <jats:italic>Tsc2<\/jats:italic> mutant GCs had hypertrophic dendritic arbors that were established by postnatal day 30. In contrast, loss of <jats:italic>Tsc2<\/jats:italic> from mature GCs had negligible effects on mTORC1, soma size, and dendrite arborization. OB transcriptome profiling revealed a network of significantly differentially expressed genes following loss of <jats:italic>Tsc2<\/jats:italic> during development that altered neural circuitry. These results demonstrate that <jats:italic>Tsc2<\/jats:italic> has a critical role in regulating neural development and shapes inhibitory GC molecular and morphological characteristics.<\/jats:p>","DOI":"10.3389\/fnmol.2022.970357","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T07:17:58Z","timestamp":1664954278000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Tsc2 shapes olfactory bulb granule cell molecular and morphological characteristics"],"prefix":"10.3389","volume":"15","author":[{"given":"Victoria A.","family":"Riley","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennie C.","family":"Holmberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aidan M.","family":"Sokolov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Feliciano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1111\/j.1468-1331.2009.02567.x","article-title":"Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature","volume":"16","author":"Adriaensen","year":"2009","journal-title":"Eur. 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