FGF8-mediated gene regulation affects regional identity in human cerebral organoids.

IF 6.4 1区生物学 Q1 BIOLOGY

eLife Pub Date : 2024-11-01 DOI:10.7554/eLife.98096

Michele Bertacchi, Gwendoline Maharaux, Agnès Loubat, Matthieu Jung, Michèle Studer

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引用次数: 0

Abstract

The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic domains, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.

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FGF8介导的基因调控影响人脑器官组织的区域特征。

形态发生因子 FGF8 可通过调节早期靶基因建立分级位置线索，传递区域性细胞反应。在模拟胎儿早期端脑发育的人体实验模型中，FGF 信号及其效应基因的作用仍然特征不清。我们使用源自 hiPSC 的脑器官组织作为体外平台，研究 FGF8 信号对神经特征和分化的影响。我们发现，FGF8处理会增加细胞的异质性，导致在多区域器官组织中共同发育出不同的端脑和间脑样域。在端脑结构域内，FGF8会影响神经祖细胞的前向和背向特性，以及GABA能神经元和谷氨酸能神经元之间的平衡，从而影响自发神经元网络活动。此外，FGF8 还能有效调节导致多种人类神经发育障碍的关键调节因子。总之，我们的研究结果表明，FGF8 信号传导直接参与了人脑器官组织的区域模式化和细胞多样性，并调节与正常和病理神经发育相关的基因。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

eLife BIOLOGY-

CiteScore

12.90

自引率

3.90%

发文量

3122

审稿时长

17 weeks

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