Simons Initiative for the Developing Brain, Hugh Robson Building, Edinburgh Medical School Biomedical Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.
Centre for Discovery Brain Sciences, Hugh Robson Building, Edinburgh Medical School Biomedical Sciences, The University of Edinburgh, Edinburgh EH8 9XD, UK.
Development. 2023 Feb 15;150(4). doi: 10.1242/dev.201227. Epub 2023 Feb 24.
Inhibitory interneurons regulate cortical circuit activity, and their dysfunction has been implicated in autism spectrum disorder (ASD). 16p11.2 microdeletions are genetically linked to 1% of ASD cases. However, few studies investigate the effects of this microdeletion on interneuron development. Using ventral telencephalic organoids derived from human induced pluripotent stem cells, we have investigated the effect of this microdeletion on organoid size, progenitor proliferation and organisation into neural rosettes, ganglionic eminence marker expression at early developmental timepoints, and expression of the neuronal marker NEUN at later stages. At early stages, deletion organoids exhibited greater variations in size with concomitant increases in relative neural rosette area and the expression of the ventral telencephalic marker COUPTFII, with increased variability in these properties. Cell cycle analysis revealed an increase in total cell cycle length caused primarily by an elongated G1 phase, the duration of which also varied more than normal. At later stages, deletion organoids increased their NEUN expression. We propose that 16p11.2 microdeletions increase developmental variability and may contribute to ASD aetiology by lengthening the cell cycle of ventral progenitors, promoting premature differentiation into interneurons.
抑制性中间神经元调节皮质回路活动，其功能障碍与自闭症谱系障碍（ASD）有关。16p11.2 微缺失与 1%的 ASD 病例有遗传关联。然而，很少有研究调查这种微缺失对中间神经元发育的影响。我们使用源自人类诱导多能干细胞的腹侧端脑类器官，研究了这种微缺失对类器官大小、祖细胞增殖和组织成神经玫瑰花结、早期发育时间点神经嵴隆起标志物表达以及晚期神经元标志物 NEUN 表达的影响。在早期阶段，缺失类器官的大小变化更大，伴随相对神经玫瑰花结面积增加和腹侧端脑标志物 COUPTFII 的表达增加，这些特性的变异性增加。细胞周期分析显示总细胞周期长度增加，主要是由于 G1 期延长，其持续时间也比正常情况变化更大。在后期阶段，缺失类器官增加了它们的 NEUN 表达。我们提出，16p11.2 微缺失增加了发育变异性，并可能通过延长腹侧祖细胞的细胞周期，促进其过早分化为中间神经元，从而导致 ASD 的发病机制。
