RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.
RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex.
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RhoA信号缺陷导致结节性硬化症患者IPSC来源的神经元轴突引导受损。
DOI：
10.1038/s41467-021-22770-4
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发表时间：
2021-05-10
影响因子：
16.6
通讯作者：
Gómez TM
中科院分区：
文献类型：
--
作者：
Catlett TS;Onesto MM;McCann AJ;Rempel SK;Glass J;Franz DN;Gómez TM
患有多发性硬化症（TSC）的患者显示在发育期间形成的神经元连接的异常布线，这可能导致TSC的症状，例如智力残疾、自闭症和癫痫。然而，还没有开发出研究人类神经元发育中轴突导向缺陷的分子基础的模型。在这里，我们从患有TSC的患者和基因工程对应物和同基因对照产生人诱导多能干细胞（hiPSC）系。通过区分hiPSC，我们发现控制神经元对预测的规范指导线索做出反应。相反，具有TSC 2杂合缺失的神经元表现出对几种排斥性线索的反应降低和轴突引导缺陷。虽然TSC 2是一个已知的MTOR依赖性蛋白质合成的关键负调节因子，但我们发现TSC 2在生长锥中通过MTOR独立的RHOA发出信号。我们的研究结果表明，TSC患者的神经网络连接缺陷可能是由于在神经元发育过程中RHOA介导的细胞骨架动力学调节的缺陷。患有多发性硬化症（TSC）的患者表现出神经元连接的异常布线。在这里，作者从TSC患者中产生iPSC衍生的神经元。TSC 2 +/−神经元显示受损的mTOR-非依赖性RhoA信号传导介导的轴突引导。
Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections formed during development which may contribute to symptoms of TSC, such as intellectual disabilities, autism, and epilepsy. Yet models examining the molecular basis for axonal guidance defects in developing human neurons have not been developed. Here, we generate human induced pluripotent stem cell (hiPSC) lines from a patient with TSC and genetically engineer counterparts and isogenic controls. By differentiating hiPSCs, we show that control neurons respond to canonical guidance cues as predicted. Conversely, neurons with heterozygous loss of TSC2 exhibit reduced responses to several repulsive cues and defective axon guidance. While TSC2 is a known key negative regulator of MTOR-dependent protein synthesis, we find that TSC2 signaled through MTOR-independent RHOA in growth cones. Our results suggest that neural network connectivity defects in patients with TSC may result from defects in RHOA-mediated regulation of cytoskeletal dynamics during neuronal development. Patients with Tuberous Sclerosis Complex (TSC) show aberrant wiring of neuronal connections. Here, the authors generate iPSC-derived neurons from patients with TSC. TSC2 +/− neurons show impaired mTOR-independent RhoA signaling-mediated axon guidance.
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影响因子：
16.6
作者：
Du, Zhong-Wei;Chen, Hong;Liu, Huisheng;Lu, Jianfeng;Qian, Kun;Huang, CindyTzu-Ling;Zhong, Xiaofen;Fan, Frank;Zhang, Su-Chun
通讯作者：
Zhang, Su-Chun
影响因子：
2.4
作者：
Choi, Seunghyuk;Sadra, Ali;Huh, Sung-Oh
通讯作者：
Huh, Sung-Oh
影响因子：
5.7
作者：
Cioni, Jean-Michel;Koppers, Max;Holt, Christine E.
通讯作者：
Holt, Christine E.
影响因子：
6.2
作者：
Alsaqati M;Heine VM;Harwood AJ
通讯作者：
Harwood AJ
影响因子：
4.8
作者：
Biever A;Valjent E;Puighermanal E
通讯作者：
Puighermanal E