Insulin-like growth factor 1 partially rescues early developmental defects caused by SHANK2 knockdown in human neurons.
Insulin-like growth factor 1 partially rescues early developmental defects caused by SHANK2 knockdown in human neurons.
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胰岛素样生长因子 1 可以部分挽救人类神经元中 SHANK2 敲低引起的早期发育缺陷
DOI：
10.4103/1673-5374.285002
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发表时间：
2020-12
影响因子：
6.1
通讯作者：
Shi LL
中科院分区：
文献类型：
--
作者：
Chen ST;Lai WJ;Zhang WJ;Chen QP;Zhou LB;So KF;Shi LL
SHANK2是一种支架蛋白，在神经元突触后密度处起蛋白锚定作用。SHANK2的遗传变异与突触功能障碍和自闭症谱系障碍的病理生理密切相关。近年来的研究表明，早期神经元发育缺陷在自闭症谱系障碍的发病机制中起作用，胰岛素样生长因子1对神经突发育有积极作用。为了研究SHANK2敲除对早期神经元发育的影响，我们利用人诱导多能干细胞建立了一个稀疏培养系统，在培养3-14天后，这些干细胞分化为神经祖细胞，并分离成单个神经元。实验组神经元感染携带红色荧光蛋白报告基因的shSHANK2慢病毒（shSHANK2组）。用携带红色荧光蛋白报告基因的重组shControl慢病毒感染对照神经元（shControl组）。利用慢病毒红色荧光蛋白信号重建了神经元的体突和神经突。然后观察两组VGLUT1+谷氨酸能神经元和TH+多巴胺能神经元的树突和运动性变化。与shControl VGLUT1+神经元相比，shSHANK2 VGLUT1+神经元的树突长度和树突数更短、更少，细胞胞体速度更高。此外，胰岛素样生长因子1处理后，shSHANK2神经元的树突长度和树突化显著增加，而细胞体细胞速度未受影响。这些结果表明，胰岛素样生长因子1可以修复形态学缺陷，但不能修复神经元运动的改变。总之，我们的研究结果表明，SHANK2缺乏会干扰早期神经元的发育，IGF1可以部分地挽救由SHANK2敲低引起的神经元缺陷。所有实验程序和方案已于2017年2月28日获得暨南大学实验动物伦理委员会批准（批准号：20170228010）。
SHANK2 is a scaffold protein that serves as a protein anchor at the postsynaptic density in neurons. Genetic variants of SHANK2 are strongly associated with synaptic dysfunction and the pathophysiology of autism spectrum disorder. Recent studies indicate that early neuronal developmental defects play a role in the pathogenesis of autism spectrum disorder, and that insulin-like growth factor 1 has a positive effect on neurite development. To investigate the effects of SHANK2 knockdown on early neuronal development, we generated a sparse culture system using human induced pluripotent stem cells, which then differentiated into neural progenitor cells after 3–14 days in culture, and which were dissociated into single neurons. Neurons in the experimental group were infected with shSHANK2 lentivirus carrying a red fluorescent protein reporter (shSHANK2 group). Control neurons were infected with scrambled shControl lentivirus carrying a red fluorescent protein reporter (shControl group). Neuronal somata and neurites were reconstructed based on the lentiviral red fluorescent protein signal. Developmental dendritic and motility changes in VGLUT1+ glutamatergic neurons and TH+ dopaminergic neurons were then evaluated in both groups. Compared with shControl VGLUT1+ neurons, the dendritic length and arborizations of shSHANK2 VGLUT1+ neurons were shorter and fewer, while cell soma speed was higher. Furthermore, dendritic length and arborization were significantly increased after insulin-like growth factor 1 treatment of shSHANK2 neurons, while cell soma speed remained unaffected. These results suggest that insulin-like growth factor 1 can rescue morphological defects, but not the change in neuronal motility. Collectively, our findings demonstrate that SHANK2 deficiency perturbs early neuronal development, and that IGF1 can partially rescue the neuronal defects caused by SHANK2 knockdown. All experimental procedures and protocols were approved by the Laboratory Animal Ethics Committee of Jinan University, China (approval No. 20170228010) on February 28, 2017.
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影响因子：
3.5
作者：
Berkel S;Tang W;Treviño M;Vogt M;Obenhaus HA;Gass P;Scherer SW;Sprengel R;Schratt G;Rappold GA
通讯作者：
Rappold GA
影响因子：
25
作者：
Lim L;Pakan JMP;Selten MM;Marques-Smith A;Llorca A;Bae SE;Rochefort NL;Marín O
通讯作者：
Marín O
根据 iPSC 衍生的形态学、生理学和整体基因表达模式对神经分化模型进行特征分析
影响因子：
4.6
作者：
Kang S;Chen X;Gong S;Yu P;Yau S;Su Z;Zhou L;Yu J;Pan G;Shi L
通讯作者：
Shi L
影响因子：
16.2
作者：
Garcia-Gonzalez, Diego;Khodosevich, Konstantin;Monyer, Hannah
通讯作者：
Monyer, Hannah
影响因子：
5.3
作者：
Ha, Seungmin;Lee, Dongwon;Kim, Eunjoon
通讯作者：
Kim, Eunjoon