Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability.,Cell Stem Cell

当前位置： X-MOL 学术 › Cell Stem Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-01-30 , DOI: 10.1016/j.stem.2019.12.013
Meiyan Wang ₁ , Pei-Chi Wei ₂ , Christina K Lim ₃ , Iryna S Gallina ₃ , Sara Marshall ₃ , Maria C Marchetto ₃ , Frederick W Alt ₄ , Fred H Gage ₁

Affiliation

The association between macrocephaly and autism spectrum disorder (ASD) suggests that the mechanisms underlying excessive neural growth could contribute to ASD pathogenesis. Consistently, neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we show that hiPSC-derived NPCs from ASD individuals with macrocephaly display an altered DNA replication program and increased DNA damage. When compared with the control NPCs, high-throughput genome-wide translocation sequencing (HTGTS) demonstrates that ASD-derived NPCs harbored elevated DNA double-strand breaks in replication stress-susceptible genes, some of which are associated with ASD pathogenesis. Our results provide a mechanism linking hyperproliferation of NPCs with the pathogenesis of ASD by disrupting long neural genes involved in cell-cell adhesion and migration.

中文翻译：

自闭症 hiPSC 模型中增加的神经祖细胞增殖会导致复制压力相关的基因组不稳定性。

大头畸形和自闭症谱系障碍 (ASD) 之间的关联表明，神经过度生长的机制可能导致 ASD 发病机制。一致地，源自具有早期发育性脑增大的 ASD 个体的人类诱导多能干细胞 (hiPSCs) 的神经祖细胞 (NPCs) 本质上比对照 NPCs 更具增殖性。在这里，我们显示来自患有大头畸形的 ASD 个体的 hiPSC 衍生的 NPC 显示出改变的 DNA 复制程序和增加的 DNA 损伤。与对照 NPC 相比，高通量全基因组易位测序 (HTGTS) 表明 ASD 衍生的 NPC 在复制应激易感基因中具有升高的 DNA 双链断裂，其中一些与 ASD 发病机制有关。

更新日期：2020-01-31

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11