STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation.
STRADA-mutant human cortical organoids model megalencephaly and exhibit delayed neuronal differentiation.
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DOI：
10.1002/dneu.22816
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发表时间：
2021-07
影响因子：
3
通讯作者：
Parent JM
中科院分区：
文献类型：
--
作者：
Dang LT;Vaid S;Lin G;Swaminathan P;Safran J;Loughman A;Lee M;Glenn T;Majolo F;Crino PB;Parent JM
涉及雷帕霉素（mTOR）通路的机械靶点的过度激活的遗传性疾病，所谓的“mTOR病”，通常表现为皮质发育畸形（MCD）、癫痫和认知障碍。mTOR通路过度激活如何导致人类皮质发育异常尚不清楚。为了研究mTOR过度活跃对皮质发育早期阶段的影响，我们重点研究了Pretzel综合征（羊水过多、巨脑畸形、症状性癫痫; PMSE综合征），这是一种由STRADA基因纯合子种系突变引起的罕见mTOR病。我们开发了一个人皮质类器官（hCO）模型的PMSE和检查形态和大小的前2周的类器官生长，和细胞类型组成的分化第2，8和12周。在第二周，PMSE hCOs比对照组扩大得更快，并显示异常的Wnt通路依赖性增加的神经花环结构。PMSE hCO还表现出延迟的神经发生，减少室管膜下区祖细胞，增加增殖和细胞死亡，以及初级纤毛的异常结构。在第8周，PMSE hCO具有较少的深层神经元。到第12周，神经发生在PMSE类器官中恢复，但它们显示出增加的外部放射状胶质细胞，这种细胞类型被认为有助于人类大脑皮层的扩张。总之，这些研究结果表明，PMSE中的巨脑畸形是由皮质发育早期神经干细胞的扩增引起的，也可能是由妊娠后期外放射状胶质细胞的增加引起的。PMSE类器官中延迟的神经元分化证明了mTOR通路在干细胞库的维持和扩增中发挥的重要作用。
Genetic diseases involving overactivation of the mechanistic target of rapamycin (mTOR) pathway, so-called “mTORopathies,” 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 STRADA gene. We developed a human cortical organoid (hCO) model of PMSE and examined morphology and size for the first 2 weeks 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-dependent 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.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
5.3
作者：
Asada, Naoyuki;Sanada, Kamon;Fukada, Yoshitaka
通讯作者：
Fukada, Yoshitaka
影响因子：
11.4
作者：
Boudeau, J;Baas, AF;Alessi, DR
通讯作者：
Alessi, DR
影响因子：
8.8
作者：
Iefremova, Vira;Manikakis, George;Ladewig, Julia
通讯作者：
Ladewig, Julia
影响因子：
64.5
作者：
Lui JH;Hansen DV;Kriegstein AR
通讯作者：
Kriegstein AR