MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

Anatoly Korotkov; Nam Suk Sim; Mark J Luinenburg; Jasper J Anink; Jackelien van Scheppingen; Till S Zimmer; Anika Bongaarts; Diede W M Broekaart; Caroline Mijnsbergen; Floor E Jansen; Wim Van Hecke; Wim G M Spliet; Peter C van Rijen; Martha Feucht; Johannes A Hainfellner; Pavel Kršek; Josef Zamecnik; Peter B Crino; Katarzyna Kotulska; Lieven Lagae; Anna C Jansen; David J Kwiatkowski; Sergiusz Jozwiak; Paolo Curatolo; Angelika Mühlebner; Jeong H Lee; James D Mills; Erwin A van Vliet; Eleonora Aronica

doi:10.1111/nan.12717

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

Anatoly Korotkov, Nam Suk Sim, Mark J Luinenburg, Jasper J Anink, Jackelien van Scheppingen, Till S Zimmer, Anika Bongaarts, Diede W M Broekaart, Caroline Mijnsbergen, Floor E Jansen, Wim Van Hecke, Wim G M Spliet, Peter C van Rijen, Martha Feucht, Johannes A Hainfellner, Pavel Kršek, Josef Zamecnik, Peter B Crino, Katarzyna Kotulska, Lieven LagaeAnna C Jansen, David J Kwiatkowski, Sergiusz Jozwiak, Paolo Curatolo, Angelika Mühlebner, Jeong H Lee, James D Mills, Erwin A van Vliet, Eleonora Aronica

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5 Citaten (Scopus)

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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, 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.

Originele taal-2	English
Pagina's (van-tot)	796-811
Aantal pagina's	16
Tijdschrift	Neuropathology and applied neurobiology
Volume	47
Nummer van het tijdschrift	6
DOI's	https://doi.org/10.1111/nan.12717
Status	Published - okt 2021

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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., Kršek, P., Zamecnik, J., Crino, P. B., Kotulska, K., ... Aronica, E. (2021). MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis. Neuropathology and applied neurobiology, 47(6), 796-811. https://doi.org/10.1111/nan.12717

Korotkov, Anatoly ; Sim, Nam Suk ; Luinenburg, Mark J ; Anink, Jasper J ; van Scheppingen, Jackelien ; Zimmer, Till S ; Bongaarts, Anika ; Broekaart, Diede W M ; Mijnsbergen, Caroline ; Jansen, Floor E ; Van Hecke, Wim ; Spliet, Wim G M ; van Rijen, Peter C ; Feucht, Martha ; Hainfellner, Johannes A ; Kršek, Pavel ; Zamecnik, Josef ; Crino, Peter B ; Kotulska, Katarzyna ; Lagae, Lieven ; Jansen, Anna C ; Kwiatkowski, David J ; Jozwiak, Sergiusz ; Curatolo, Paolo ; Mühlebner, Angelika ; Lee, Jeong H ; Mills, James D ; van Vliet, Erwin A ; Aronica, Eleonora. / MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis. In: Neuropathology and applied neurobiology. 2021 ; Vol. 47, Nr. 6. blz. 796-811.

@article{e54bff336ee54eac9745d3a8c08ff9db,

title = "MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis",

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, 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.",

author = "Anatoly Korotkov and Sim, {Nam Suk} and Luinenburg, {Mark J} and Anink, {Jasper J} and {van Scheppingen}, Jackelien and Zimmer, {Till S} and Anika Bongaarts and Broekaart, {Diede W M} and Caroline Mijnsbergen and Jansen, {Floor E} and {Van Hecke}, Wim and Spliet, {Wim G M} and {van Rijen}, {Peter C} and Martha Feucht and Hainfellner, {Johannes A} and Pavel Kr{\v s}ek and Josef Zamecnik and Crino, {Peter B} and Katarzyna Kotulska and Lieven Lagae and Jansen, {Anna C} and Kwiatkowski, {David J} and Sergiusz Jozwiak and Paolo Curatolo and Angelika M{\"u}hlebner and Lee, {Jeong H} and Mills, {James D} and {van Vliet}, {Erwin A} and Eleonora Aronica",

note = "{\textcopyright} 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.",

year = "2021",

month = oct,

doi = "10.1111/nan.12717",

language = "English",

volume = "47",

pages = "796--811",

journal = "Neuropathology and applied neurobiology",

issn = "0305-1846",

publisher = "Wiley",

number = "6",

}

Korotkov, A, Sim, NS, Luinenburg, MJ, Anink, JJ, van Scheppingen, J, Zimmer, TS, Bongaarts, A, Broekaart, DWM, Mijnsbergen, C, Jansen, FE, Van Hecke, W, Spliet, WGM, van Rijen, PC, Feucht, M, Hainfellner, JA, Kršek, P, Zamecnik, J, Crino, PB, Kotulska, K, Lagae, L, Jansen, AC, Kwiatkowski, DJ, Jozwiak, S, Curatolo, P, Mühlebner, A, Lee, JH, Mills, JD, van Vliet, EA & Aronica, E 2021, 'MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis', Neuropathology and applied neurobiology, vol. 47, nr. 6, blz. 796-811. https://doi.org/10.1111/nan.12717

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis. / Korotkov, Anatoly; Sim, Nam Suk; Luinenburg, Mark J; Anink, Jasper J; van Scheppingen, Jackelien; Zimmer, Till S; Bongaarts, Anika; Broekaart, Diede W M; Mijnsbergen, Caroline; Jansen, Floor E; Van Hecke, Wim; Spliet, Wim G M; van Rijen, Peter C; Feucht, Martha; Hainfellner, Johannes A; Kršek, Pavel; Zamecnik, Josef; Crino, Peter B; Kotulska, Katarzyna; Lagae, Lieven; Jansen, Anna C; Kwiatkowski, David J; Jozwiak, Sergiusz; Curatolo, Paolo; Mühlebner, Angelika; Lee, Jeong H; Mills, James D; van Vliet, Erwin A; Aronica, Eleonora.

In: Neuropathology and applied neurobiology, Vol. 47, Nr. 6, 10.2021, blz. 796-811.

Onderzoeksoutput: Article › peer review

TY - JOUR

T1 - MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

AU - Korotkov, Anatoly

AU - Sim, Nam Suk

AU - Luinenburg, Mark J

AU - Anink, Jasper J

AU - van Scheppingen, Jackelien

AU - Zimmer, Till S

AU - Bongaarts, Anika

AU - Broekaart, Diede W M

AU - Mijnsbergen, Caroline

AU - Jansen, Floor E

AU - Van Hecke, Wim

AU - Spliet, Wim G M

AU - van Rijen, Peter C

AU - Feucht, Martha

AU - Hainfellner, Johannes A

AU - Kršek, Pavel

AU - Zamecnik, Josef

AU - Crino, Peter B

AU - Kotulska, Katarzyna

AU - Lagae, Lieven

AU - Jansen, Anna C

AU - Kwiatkowski, David J

AU - Jozwiak, Sergiusz

AU - Curatolo, Paolo

AU - Mühlebner, Angelika

AU - Lee, Jeong H

AU - Mills, James D

AU - van Vliet, Erwin A

AU - Aronica, Eleonora

PY - 2021/10

Y1 - 2021/10

N2 - 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, 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.

AB - 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, 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.

UR - http://www.scopus.com/inward/record.url?scp=85107727171&partnerID=8YFLogxK

U2 - 10.1111/nan.12717

DO - 10.1111/nan.12717

M3 - Article

C2 - 33942341

VL - 47

SP - 796

EP - 811

JO - Neuropathology and applied neurobiology

JF - Neuropathology and applied neurobiology

SN - 0305-1846

IS - 6

ER -

MicroRNA-34a activation in tuberous sclerosis complex during early brain development may lead to impaired corticogenesis

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