MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis
Korotkov, A; Sim, N S; Luinenburg, M J; Anink, J J; van Scheppingen, J; Zimmer, T S; Bongaarts, A; Broekaart, D W M; Mijnsbergen, C; Jansen, F E; Van Hecke, W; Spliet, W G M; van Rijen, P C; Feucht, M; Hainfellner, J A; Krsek, P; Zamecnik, J; Crino, P B; Kotulska, K; Lagae, L; Jansen, A C; Kwiatkowski, D J; Jozwiak, S; Curatolo, P; Mühlebner, A; Lee, J H; Mills, J D; van Vliet, E A; Aronica, E
(2021) Neuropathology and Applied Neurobiology, volume 47, issue 6, pp. 796 - 811
(Article)
Abstract
AIMS: 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,
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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.
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Keywords: mechanistic target of rapamycin, migration, miRNA, neurodevelopmental disorder, TSC, Clinical Neurology, Neurology, Physiology (medical), Pathology and Forensic Medicine, Histology, Journal Article
ISSN: 0305-1846
Publisher: Wiley-Blackwell
Note: Funding Information: no. 952455 (EpiEpiNet, EA, EAvV, JM) and the Dutch Epilepsy Foundation, project number 20‐02 (AM,MJL). Funding Information: The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007‐2013) under grant agreement 602102 (EPITARGET; EAvV, EA) and 602391 (EPISTOP; EA, MF, PK, KK, LL, ACJ, DJK, SJ, PC, AM, JDM, AM, JvS, FEJ), the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska‐Curie grant agreement 642881 (ECMED; AK, EA, EAvV) and 722053 (EU‐GliaPhD; TSZ, EA, EAvV), as well as 952455 (EpiEpiNet, EA, EAvV, JM) and the Dutch Epilepsy Foundation, project number 20‐02 (AM, MJL). Funding Information: The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) under grant agreement 602102 (EPITARGET; EAvV, EA) and 602391 (EPISTOP; EA, MF, PK, KK, LL, ACJ, DJK, SJ, PC, AM, JDM, AM, JvS, FEJ), the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement 642881 (ECMED; AK, EA, EAvV) and 722053 (EU-GliaPhD; TSZ, EA, EAvV), as well as 952455 (EpiEpiNet, EA, EAvV, JM) and the Dutch Epilepsy Foundation, project number 20-02 (AM, MJL). The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) under grant agreement 602102 (EPITARGET; EAvV, EA) and 602391 (EPISTOP; EA, MF, PK, KK, LL, ACJ, DJK, SJ, PC, AM, JDM, AM, JvS, FEJ), the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant agreement no. 642881 (ECMED; AK, EA, EAvV) and no. 722053 (EU-GliaPhD; TSZ, EA, EAvV), as well as no. 952455 (EpiEpiNet, EA, EAvV, JM) and the Dutch Epilepsy Foundation, project number 20-02 (AM,MJL). Funding Information: Horizon 2020 Research and Innovation Programme under the Marie Sklodowska‐Curie grant Funding Information: The research leading to these results has received funding from the European Union's Seventh Publisher Copyright: © 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
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