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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DOI：
10.1038/s41380-021-01182-2
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发表时间：
2022-03
影响因子：
11
通讯作者：
Syed, Yasir Ahmed
中科院分区：
文献类型：
--
作者：
Chapman, Gareth;Alsaqati, Mouhamed;Lunn, Sharna;Singh, Tanya;Linden, Stefanie C.;Linden, David E. J.;van den Bree, Marianne B. M.;Ziller, Mike;Owen, Michael J.;Hall, Jeremy;Harwood, Adrian J.;Syed, Yasir Ahmed
1q21.1位点的拷贝数变异（CNV）与人类一系列神经发育和精神疾病有关，包括头部大小异常和运动缺陷。然而，这些CNVs（删除和复制）对神经元发育的功能影响尚不清楚。为了确定1q21.1位点CNV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了诱导多能干细胞，并将其分化为功能性皮质神经元。我们发现，具有1q21.1缺失或重复的神经元在增殖、分化潜能、神经元成熟、突触密度和功能活性方面表现出互惠表型。1q21.1位点的缺失也与皮质下层标记物的表达增加有关。这种差异在1q21.1缺失的小鼠模型中保持不变，表现出皮质发生改变。重要的是，我们发现1q21.1缺失和重复的神经元与钙通道的差异表达有关，并证明1q21.1缺失或重复的神经元的生理缺陷可以通过靶向Ca2+通道活性进行药理学调节。这些发现为1q21.1相关脑部疾病的神经病理机制提供了生物学视角，并指出了治疗干预的潜在靶点。
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.
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影响因子：
30.8
作者：
Krumm, Niklas;Turner, Tychele N.;Baker, Carl;Vives, Laura;Mohajeri, Kiana;Witherspoon, Kali;Raja, Archana;Coe, Bradley P.;Stessman, Holly A.;He, Zong-Xiao;Leal, Suzanne M.;Bernier, Raphael;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
11
作者：
Cipriani, A.;Saunders, K.;Attenburrow, M-J;Stefaniak, J.;Panchal, P.;Stockton, S.;Lane, T. A.;Tunbridge, E. M.;Geddes, J. R.;Harrison, P. J.
通讯作者：
Harrison, P. J.
影响因子：
8.8
作者：
Meyer, Katharina;Feldman, Heather M.;Yankner, Bruce A.
通讯作者：
Yankner, Bruce A.
影响因子：
6.8
作者：
Niarchou, Maria;Chawner, Samuel J. R. A.;van den Bree, Marianne B. M.
通讯作者：
van den Bree, Marianne B. M.
影响因子：
2.1
作者：
MACDONALD, JF;SCHNEIDERMAN, JH
通讯作者：
SCHNEIDERMAN, JH