胎儿酒精综合症（FAS）影响了超过90％的患儿，导致严重的眼球异常，如小眼和视神经发育不良。在妊娠的早期阶段，神经视网膜神经发生的开始代表了人眼发育的关键时期，同时由于缺乏意识，使胚胎视网膜结构在发育过程中暴露于产前乙醇暴露的最高风险。尽管这一时期的重要性至关重要，但短期乙醇暴露对人类神经视网膜发育过程的确切影响和潜在机制仍然不清楚。在本研究中，我们利用人胚胎干细胞衍生的视网膜器官样体（hROs）复制了初始视网膜神经发生的过程，并发现1％（体积/体积）乙醇通过诱导强烈的细胞死亡和视网膜神经节细胞分化缺陷来减缓hROs的生长。大规模RNA-seq分析和两光子显微镜活体钙成像揭示乙醇诱导的RYR1和CACNA1S的下调导致钙信号动态变化。此外，钙结合蛋白RET作为钙信号通路的下游效应基因之一，有协同的作用，集成乙醇和钙信号来阻止神经元分化并引起细胞死亡。总之，我们的研究展示了乙醇对人类胚胎神经视网膜初始神经发生的影响和分子机制，为FAS的眼睛表型提供了新的解释，并可能为易感人群提供预防措施的指导。 © 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Fetal Alcohol Syndrome (FAS) affects a significant proportion, exceeding 90%, of afflicted children, leading to severe ocular aberrations such as microphthalmia and optic nerve hypoplasia. During the early stages of pregnancy, the commencement of neural retina neurogenesis represents a critical period for human eye development, concurrently exposing the developing retinal structures to the highest risk of prenatal ethanol exposure due to a lack of awareness. Despite the paramount importance of this period, the precise influence and underlying mechanisms of short-term ethanol exposure on the developmental process of the human neural retina have remained largely elusive. In this study, we utilize the human embryonic stem cells derived retinal organoids (hROs) to recapitulate the initial retinal neurogenesis and find that 1% (v/v) ethanol slows the growth of hROs by inducing robust cell death and retinal ganglion cell differentiation defect. Bulk RNA-seq analysis and two-photon microscope live calcium imaging reveal altered calcium signaling dynamics derived from ethanol-induced down-regulation of RYR1 and CACNA1S. Moreover, the calcium-binding protein RET, one of the downstream effector genes of the calcium signaling pathway, synergistically integrates ethanol and calcium signals to abort neuron differentiation and cause cell death. To sum up, our study illustrates the effect and molecular mechanism of ethanol on the initial neurogenesis of the human embryonic neural retina, providing a novel interpretation of the ocular phenotype of FAS and potentially informing preventative measures for susceptible populations.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.