Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome
Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome
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使用诱导多能干细胞研究 1q21.1 缺失和重复综合征中的人类神经元表型
DOI：
10.1101/2021.02.08.430246
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Chapman G
中科院分区：
文献类型：
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作者：
Chapman G
1q21.1基因座的拷贝数变异（CNV）与人类的一系列神经发育和精神疾病相关，包括头部大小和运动缺陷的异常。然而，这些CNV（缺失和复制）对神经元发育的功能后果仍然未知。为了确定CNV在1q21.1基因座对神经元发育的影响，我们从携带1q21.1缺失或重复的个体中产生诱导多能干细胞，并将其分化为功能性皮质神经元。我们发现，1q21.1缺失或重复的神经元显示相对于增殖，分化潜能，神经元成熟，突触密度和功能活动的相互表型。1q21.1位点的缺失也与较低皮质层标记物的表达增加相关。这种差异在1q21.1缺失的小鼠模型中是保守的，该模型显示皮质生成改变。重要的是，我们发现，与1q21.1缺失和复制的神经元与钙通道的差异表达，并证明，在神经元与1q21.1缺失或复制的生理缺陷可以通过靶向钙离子通道活性的间接调制。这些发现为1q21.1相关脑疾病的神经病理学机制提供了生物学见解，并为治疗干预提供了潜在靶点。
Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.