An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome
An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome
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DOI：
10.1016/j.celrep.2017.03.047
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发表时间：
2017-04-04
期刊：
影响因子：
8.8
通讯作者：
Ladewig, Julia
中科院分区：
文献类型：
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作者：
Iefremova, Vira;Manikakis, George;Ladewig, Julia
Miller-Dieker综合征（MDS）是由染色体17p13.3的杂合缺失引起的，涉及基因LIS1和YWHAE（编码14.3.3 epsilon），并导致皮质发育过程中的畸形。在这里，我们使用患者特异性前脑型类器官来研究与MDS相关的病理变化。患者源性类器官的大小显著减小，这一变化伴随着心室区径向胶质细胞（vRGCs）从对称细胞分裂到不对称细胞分裂的转变。我们还观察到vrgc中微管网络组织的改变和皮质生态位结构的破坏，包括细胞粘附分子的表达改变。这些表型变化导致n-钙粘蛋白/ β -连环蛋白信号轴的非细胞自主干扰。重新安装活跃的β -连环蛋白信号可以挽救分裂模式并改善生长缺陷。我们的数据定义了LIS1和14.3.3 epsilon在维持皮质生态位中的作用，并强调了基于器官的系统在体外模拟复杂细胞-细胞相互作用方面的实用性。
Miller-Dieker syndrome (MDS) is caused by a heterozygous deletion of chromosome 17p13.3 involving the genes LIS1 and YWHAE (coding for 14.3.3 epsilon) and leads to malformations during cortical development. Here, we used patient-specific forebrain-type organoids to investigate pathological changes associated with MDS. Patient-derived organoids are significantly reduced in size, a change accompanied by a switch from symmetric to asymmetric cell division of ventricular zone radial glia cells (vRGCs). Alterations in microtubule network organization in vRGCs and a disruption of cortical niche architecture, including altered expression of cell adhesion molecules, are also observed. These phenotypic changes lead to a non-cell-autonomous disturbance of the N-cadherin/beta-catenin signaling axis. Reinstalling active beta-catenin signaling rescues division modes and ameliorates growth defects. Our data define the role of LIS1 and 14.3.3 epsilon in maintaining the cortical niche and highlight the utility of organoid-based systems for modeling complex cell-cell interactions in vitro.