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

被引：10

作者：

Korotkov, Anatoly ^{[1
]}

Sim, Nam Suk ^{[2
]}

Luinenburg, Mark J. ^{[1
]}

Anink, Jasper J. ^{[1
]}

van Scheppingen, Jackelien ^{[1
,3
]}

Zimmer, Till S. ^{[1
]}

Bongaarts, Anika ^{[1
]}

Broekaart, Diede W. M. ^{[1
]}

Mijnsbergen, Caroline ^{[1
]}

Jansen, Floor E. ^{[4
]}

Van Hecke, Wim ^{[5
]}

Spliet, Wim G. M. ^{[5
]}

van Rijen, Peter C. ^{[6
]}

Feucht, Martha ^{[7
]}

Hainfellner, Johannes A. ^{[8
]}

Krsek, Pavel ^{[9
,10
]}

Zamecnik, Josef ^{[10
,11
]}

Crino, Peter B. ^{[12
]}

Kotulska, Katarzyna ^{[13
]}

Lagae, Lieven ^{[14
]}

Jansen, Anna C. ^{[15
]}

Kwiatkowski, David J. ^{[16
]}

Jozwiak, Sergiusz ^{[13
,17
]}

Curatolo, Paolo ^{[18
]}

Muhlebner, Angelika ^{[1
]}

Lee, Jeong H. ^{[2
,19
]}

Mills, James D. ^{[1
,20
,21
]}

van Vliet, Erwin A. ^{[1
,22
]}

Aronica, Eleonora ^{[1
,23
]}

机构：

[1] Univ Amsterdam, Dept Neuro Pathol, Amsterdam Neurosci, Amsterdam UMC, Amsterdam, Netherlands

[2] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea

[3] Netherlands Inst Neurosci, Dept Neuroimmunol, Amsterdam, Netherlands

[4] Univ Med Ctr Utrecht, Dept Paediat Neurol, Utrecht, Netherlands

[5] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands

[6] Rudolf Magnus Inst Neurosci, Brain Ctr, Univ Med Ctr, Utrecht, Netherlands

[7] Med Univ Vienna, Dept Pediat, Vienna, Austria

[8] Med Univ Vienna, Inst Neurol, Vienna, Austria

[9] 2nd Fac Med, Dept Pediat Neurol, Prague, Czech Republic

[10] Motol Univ Hosp, Prague, Czech Republic

[11] 2nd Fac Med, Dept Pathol & Mol Med, Prague, Czech Republic

[12] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA

[13] Childrens Mem Hlth Inst, Dept Neurol & Epileptol, Warsaw, Poland

[14] Univ Hosp KU Leuven, Dept Dev & Regenerat, Sect Pediat Neurol, Leuven, Belgium

[15] Univ Ziekenhuis Brussel, Pediat Neurol Unit, Brussels, Belgium

[16] Harvard Med Sch, Brigham & Womens Hosp, Boston, MA 02115 USA

[17] Med Univ Warsaw, Dept Child Neurol, Warsaw, Poland

[18] Tor Vergata Univ, Syst Med Dept, Child Neurol & Psychiat Unit, Rome, Italy

[19] SoVarGen Inc, Daejeon, South Korea

[20] UCL, Dept Clin & Expt Epilepsy, London, England

[21] Chalfont Ctr Epilepsy, Gerrards Cross, England

[22] Univ Amsterdam, Ctr Neurosci, Swammerdam Inst Life Sci, Amsterdam, Netherlands

[23] Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands

来源：

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY | 2021年 / 47卷 / 06期

基金：

欧盟地平线“2020”;

关键词：

mechanistic target of rapamycin; migration; miRNA; neurodevelopmental disorder; TSC; PRENATAL-DIAGNOSIS; CARDIAC RHABDOMYOMAS; INCREASED EXPRESSION; CEREBRAL-LESIONS; GENE-EXPRESSION; FETAL-BRAIN; P53; TARGET; MIR-34A; RNA; TSC;

D O I：

10.1111/nan.12717

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：796 / 811

页数：16

共 74 条

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