Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Transl Psychiatry. 2018 Apr 12;8(1):77. doi: 10.1038/s41398-018-0122-x.
The development of three-dimensional culture methods has allowed for the study of developing cortical morphology in human cells. This provides a new tool to study the neurodevelopmental consequences of disease-associated mutations. Here, we study the effects of isogenic DISC1 mutation in cerebral organoids. DISC1 has been implicated in psychiatric disease based on genetic studies, including its interruption by a balanced translocation that increases the risk of major mental illness. Isogenic wild-type and DISC1-disrupted human-induced pluripotent stem cells were used to generate cerebral organoids, which were then examined for morphology and gene expression. We show that DISC1-mutant cerebral organoids display disorganized structural morphology and impaired proliferation, which is phenocopied by WNT agonism and rescued by WNT antagonism. Furthermore, there are many shared changes in gene expression with DISC1 disruption and WNT agonism, including in neural progenitor and cell fate markers, regulators of neuronal migration, and interneuron markers. These shared gene expression changes suggest mechanisms for the observed morphologic dysregulation with DISC1 disruption and points to new avenues for future studies. The shared changes in three-dimensional cerebral organoid morphology and gene expression with DISC1 interruption and WNT agonism further strengthens the link between DISC1 mutation, abnormalities in WNT signaling, and neuropsychiatric disease.
三维培养方法的发展使得研究人类细胞皮质形态的发育成为可能。这为研究与疾病相关突变的神经发育后果提供了新的工具。在这里，我们研究了同源性 DISC1 突变对大脑类器官的影响。基于遗传研究，DISC1 与精神疾病有关，包括其被平衡易位所打断，这增加了患重大精神疾病的风险。使用同基因野生型和 DISC1 缺失的人类诱导多能干细胞生成大脑类器官，然后检查其形态和基因表达。我们发现，DISC1 突变的大脑类器官显示出结构形态紊乱和增殖受损，这可以被 WNT 激动剂模拟，被 WNT 拮抗剂挽救。此外，DISC1 缺失和 WNT 激动剂引起的基因表达变化有许多共同之处，包括神经祖细胞和细胞命运标志物、神经元迁移调节剂和中间神经元标志物。这些共同的基因表达变化表明了与 DISC1 缺失引起的形态失调有关的机制，并为未来的研究指明了新的途径。DISC1 中断和 WNT 激动剂引起的三维大脑类器官形态和基因表达的共同变化进一步加强了 DISC1 突变、WNT 信号异常与神经精神疾病之间的联系。
