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dc.contributor.authorKorotkov, Anatoly
dc.contributor.authorSim, Nam Suk
dc.contributor.authorLuinenburg, Mark J
dc.contributor.authorAnink, Jasper J
dc.contributor.authorvan Scheppingen, Jackelien
dc.contributor.authorZimmer, Till S
dc.contributor.authorBongaarts, Anika
dc.contributor.authorBroekaart, Diede W M
dc.contributor.authorMijnsbergen, Caroline
dc.contributor.authorJansen, Floor E
dc.contributor.authorVan Hecke, Wim
dc.contributor.authorSpliet, Wim G M
dc.contributor.authorvan Rijen, Peter C
dc.contributor.authorFeucht, Martha
dc.contributor.authorHainfellner, Johannes A
dc.contributor.authorKršek, Pavel
dc.contributor.authorZamecnik, Josef
dc.contributor.authorCrino, Peter B
dc.contributor.authorKotulska, Katarzyna
dc.contributor.authorLagae, Lieven
dc.contributor.authorJansen, Anna C
dc.contributor.authorKwiatkowski, David J
dc.contributor.authorJozwiak, Sergiusz
dc.contributor.authorCuratolo, Paolo
dc.contributor.authorMühlebner, Angelika
dc.contributor.authorLee, Jeong H
dc.contributor.authorMills, James D
dc.contributor.authorvan Vliet, Erwin A
dc.contributor.authorAronica, Eleonora
dc.date.accessioned2021-06-21T13:08:25Z
dc.date.available2021-06-21T13:08:25Z
dc.date.issued2021-05-03
dc.identifier.urihttp://hdl.handle.net/10713/16045
dc.description.abstractAims: Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA-34a (miR-34a) among the most upregulated miRs in tubers. Here, we characterised miR-34a expression in tubers with the focus on the early brain development and assessed the regulation of mTORC1 pathway and corticogenesis by miR-34a. Methods: We analysed the expression of miR-34a in resected cortical tubers (n = 37) compared with autopsy-derived control tissue (n = 27). The effect of miR-34a overexpression on corticogenesis was assessed in mice at E18. The regulation of the mTORC1 pathway and the expression of the bioinformatically predicted target genes were assessed in primary astrocyte cultures from three patients with TSC and in SH-SY5Y cells following miR-34a transfection. Results: The peak of miR-34a overexpression in tubers was observed during infancy, concomitant with the presence of pathological markers, particularly in giant cells and dysmorphic neurons. miR-34a was also strongly expressed in foetal TSC cortex. Overexpression of miR-34a in mouse embryos decreased the percentage of cells migrated to the cortical plate. The transfection of miR-34a mimic in TSC astrocytes negatively regulated mTORC1 and decreased the expression of the target genes RAS related (RRAS) and NOTCH1. Conclusions: MicroRNA-34a is most highly overexpressed in tubers during foetal and early postnatal brain development. miR-34a can negatively regulate mTORC1; however, it may also contribute to abnormal corticogenesis in TSC.en_US
dc.description.urihttps://doi.org/10.1111/nan.12717en_US
dc.language.isoenen_US
dc.publisherWiley-Blackwellen_US
dc.relation.ispartofNeuropathology and Applied Neurobiologyen_US
dc.rights© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.en_US
dc.subjectTSCen_US
dc.subjectmechanistic target of rapamycinen_US
dc.subjectmiRNAen_US
dc.subjectmigrationen_US
dc.subjectneurodevelopmental disorderen_US
dc.titleMicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesisen_US
dc.typeArticleen_US
dc.identifier.doi10.1111/nan.12717
dc.identifier.pmid33942341
dc.source.countryEngland


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