{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:06:01Z","timestamp":1790744761595,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS109289"],"award-info":[{"award-number":["NS109289"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Developmental Neurobiology"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genetic diseases involving overactivation of the mechanistic target of rapamycin (mTOR) pathway, so\u2010called \u201cmTORopathies,\u201d often manifest with malformations of cortical development (MCDs), epilepsy, and cognitive impairment. How mTOR pathway hyperactivation results in abnormal human cortical development is poorly understood. To study the effect of mTOR hyperactivity on early stages of cortical development, we focused on Pretzel Syndrome (polyhydramnios, megalencephaly, symptomatic epilepsy; PMSE syndrome), a rare mTORopathy caused by homozygous germline mutations in the <jats:italic>STRADA<\/jats:italic> gene. We developed a human cortical organoid (hCO) model of PMSE and examined morphology and size for the first 2\u00a0weeks of organoid growth, and cell type composition at weeks 2, 8, and 12 of differentiation. In the second week, PMSE hCOs enlarged more rapidly than controls and displayed an abnormal Wnt pathway\u2010dependent increase in neural rosette structures. PMSE hCOs also exhibited delayed neurogenesis, decreased subventricular zone progenitors, increased proliferation and cell death, and an abnormal architecture of primary cilia. At week 8, PMSE hCOs had fewer deep layer neurons. By week 12, neurogenesis recovered in PMSE organoids, but they displayed increased outer radial glia, a cell type thought to contribute to the expansion of the human cerebral cortex. Together, these findings suggest that megalencephaly in PMSE arises from the expansion of neural stem cells in early corticogenesis and potentially also from increased outer radial glial at later gestational stages. The delayed neuronal differentiation in PMSE organoids demonstrates the important role the mTOR pathway plays in the maintenance and expansion of the stem cell pool.<\/jats:p>","DOI":"10.1002\/dneu.22816","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T02:40:56Z","timestamp":1614048056000},"page":"696-709","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["<i>STRADA<\/i>\u2010mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation"],"prefix":"10.1002","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4853-4952","authenticated-orcid":false,"given":"Louis T.","family":"Dang","sequence":"first","affiliation":[{"name":"Department of Pediatrics Michigan Medicine Ann Arbor MI USA"},{"name":"Department of Neurology Michigan Medicine Ann Arbor MI USA"},{"name":"Michigan Neuroscience Institute Michigan Medicine Ann Arbor MI 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