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dc.contributor.authorIffland, II, P.H.
dc.contributor.authorBarnes, A.E.
dc.contributor.authorBaybis, M.
dc.contributor.authorCrino, P.B.
dc.date.accessioned2020-06-01T18:26:13Z
dc.date.available2020-06-01T18:26:13Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85085199060&doi=10.3389%2ffncel.2020.00122&partnerID=40&md5=36c6b6d7d4828ad248831b17fce775cf
dc.identifier.urihttp://hdl.handle.net/10713/12904
dc.description.abstractmTORopathies are a heterogeneous group of neurological disorders characterized by malformations of cortical development (MCD), enhanced cellular mechanistic target of rapamycin (mTOR) signaling, and epilepsy that results from mutations in mTOR pathway regulatory genes. Homozygous mutations (del exon 9–13) in the pseudokinase STE20-related kinase adaptor alpha (STRAD-α; STRADA), an mTOR modulator, are associated with Pretzel Syndrome (PS), a neurodevelopmental disorder within the Old Order Mennonite Community characterized by megalencephaly, intellectual disability, and intractable epilepsy. To study the cellular mechanisms of STRADA loss, we generated CRISPR-edited Strada mouse N2a cells, a germline mouse Strada knockout (KO−/−) strain, and induced pluripotent stem cell (iPSC)-derived neurons from PS individuals harboring the STRADA founder mutation. Strada KO in vitro leads to enhanced mTOR signaling and iPSC-derived neurons from PS individuals exhibit enhanced cell size and mTOR signaling activation, as well as subtle alterations in electrical firing properties e.g., increased input resistance, a more depolarized resting membrane potential, and decreased threshold for action potential (AP) generation. Strada−/− mice exhibit high rates of perinatal mortality and out of more than 100 litters yielding both WT and heterozygous pups, only eight Strada−/− animals survived past P5. Strada−/− mice are hypotonic and tremulous. Histopathological examination (n = 5 mice) revealed normal gross brain organization and lamination but all had ventriculomegaly. Ectopic neurons were seen in all five Strada−/− brains within the subcortical white matter mirroring what is observed in human PS brain tissue. These distinct experimental platforms demonstrate that STRADA modulates mTOR signaling and is a key regulator of cell size, neuronal excitability, and cortical lamination. Copyright 2020 The Authors.en_US
dc.description.sponsorshipFunding from National Institute of Neurological Disorders and Stroke (NINDS) R01NS094596, R01NS099452, R21NS087181-01, K08NS109289 and a Ravitz Advancement Award from the Department of Pediatrics, Michigan Medicine.en_US
dc.description.urihttps://doi.org/10.3389/fncel.2020.00122en_US
dc.language.isoen_USen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.ispartofFrontiers in Cellular Neuroscience
dc.subjectepilepsyen_US
dc.subjectiPSCen_US
dc.subjectmegalencephalyen_US
dc.subjectmouseen_US
dc.subjectmTORen_US
dc.subjectseizureen_US
dc.titleMultimodal Analysis of STRADA Function in Brain Developmenten_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fncel.2020.00122


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