Modeling Down Syndrome with Patient iPSCs Reveals Cellular and Migration Deficits of GABAergic Neurons.
Modeling Down Syndrome with Patient iPSCs Reveals Cellular and Migration Deficits of GABAergic Neurons.
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使用患者 iPSC 进行唐氏综合症建模揭示了 GABA 能神经元的细胞和迁移缺陷。
DOI：
10.1016/j.stemcr.2018.02.001
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发表时间：
2018-04-10
影响因子：
5.9
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Huo HQ;Qu ZY;Yuan F;Ma L;Yao L;Xu M;Hu Y;Ji J;Bhattacharyya A;Zhang SC;Liu Y
唐氏综合征（DS）患者大脑皮层的中间神经元较少，但其潜在机制尚不清楚。通过对DS和整倍体诱导多能干细胞（iPSCs）生成的皮质中间神经元的形态分析，我们发现DS GABA神经元更小，神经元突起更少。calretinin在calbindin GABA神经元上的比例降低，神经元迁移能力下降。将DS - gaba能祖细胞移植到小鼠内侧隔膜后，这些表型得以复制。基因表达谱揭示了细胞迁移途径的改变，PAK1途径的纠正减轻了细胞在体外的迁移缺陷。这些结果表明，退行性椎体变性患者大脑皮层和海马的中间神经元数量减少可能是退行性椎体变性患者gaba能神经元迁移受损的原因之一。DS ipsc衍生的GABA中间神经元在体外和体内表现出细胞缺陷DS GABA中间神经元在体外和体内表现出迁移减少，RNA-seq揭示了PAK1在DS中间神经元中的表达被破坏。调控PAK1通路可以修复迁移缺陷。Liu及其同事在体外和体内研究表明，唐氏综合征ipsc衍生的GABA能中间神经元在形态上的复杂性较低，迁移受损。
The brain of Down syndrome (DS) patients exhibits fewer interneurons in the cerebral cortex, but its underlying mechanism remains unknown. By morphometric analysis of cortical interneurons generated from DS and euploid induced pluripotent stem cells (iPSCs), we found that DS GABA neurons are smaller and with fewer neuronal processes. The proportion of calretinin over calbindin GABA neurons is reduced, and the neuronal migration capacity is decreased. Such phenotypes were replicated following transplantation of the DS GABAergic progenitors into the mouse medial septum. Gene expression profiling revealed altered cell migratory pathways, and correction of the PAK1 pathway mitigated the cell migration deficit in vitro. These results suggest that impaired migration of DS GABAergic neurons may contribute to the reduced number of interneurons in the cerebral cortex and hippocampus in DS patients. DS iPSC-derived GABA interneurons show cellular deficits DS GABA interneurons exhibit decreased migration in vitro and in vivo RNA-seq reveals that expression of PAK1 is disrupted in the DS interneurons Regulation of PAK1 pathway rescues the defects of migration In this article, Liu and colleagues show that Down syndrome iPSC-derived GABAergic interneurons exhibit less complexity in morphology and impaired migration both in vitro and in vivo.
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影响因子：
46.9
作者：
通讯作者：
--
影响因子：
3.6
作者：
Qin S;Ware SM;Waclaw RR;Campbell K
通讯作者：
Campbell K
影响因子：
3.5
作者：
Contestabile, Andrea;Fila, Tatiana;Ciani, Elisabetta
通讯作者：
Ciani, Elisabetta
影响因子：
3.7
作者：
Perez-Nunez, Ramon;Barraza, Natalia;Caviedes, Pablo
通讯作者：
Caviedes, Pablo
DOI：
10.1093/cercor/bht254
发表时间：
2015-03
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Al-Jaberi N;Lindsay S;Sarma S;Bayatti N;Clowry GJ
通讯作者：
Clowry GJ