Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX, USA; Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX, USA.
Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, Bryan, TX, USA; Women's Health in Neuroscience Program, Texas A&M University Health Science Center, Bryan, TX, USA.
Neurotoxicol Teratol. 2021 Jan-Feb;83:106943. doi: 10.1016/j.ntt.2020.106943. Epub 2020 Nov 20.
Prenatal ethanol exposure can result in loss of neural stem cells (NSCs) and decreased brain growth. Here, we assessed whether a noncoding RNA (ncRNA) related to the NSC self-renewal factor Oct4/Pou5f1, and transcribed from a processed pseudogene locus on mouse chromosome 9 (mOct4pg9), contributed to the loss of NSCs due to ethanol. Mouse fetal cortical-derived NSCs, cultured ex vivo to mimic the early neurogenic environment of the fetal telencephalon, expressed mOct4pg9 ncRNA at significantly higher levels than the parent Oct4/Pou5f1 mRNA. Ethanol exposure increased expression of mOct4pg9 ncRNA, but decreased expression of Oct4/Pou5f1. Gain- and loss-of-function analyses indicated that mOct4pg9 overexpression generally mimicked effects of ethanol exposure, resulting in increased proliferation and expression of transcripts associated with neural maturation. Moreover, mOct4pg9 associated with Ago2 and with miRNAs, including the anti-proliferative miR-328-3p, whose levels were reduced following mOct4pg9 overexpression. Finally, mOct4pg9 inhibited Oct4/Pou5f1-3'UTR-dependent protein translation. Consistent with these observations, data from single-cell transcriptome analysis showed that mOct4pg9-expressing progenitors lack Oct4/Pou5f1, but instead overexpress transcripts for increased mitosis, suggesting initiation of transit amplification. Collectively, these data suggest that the inhibitory effects of ethanol on brain development are explained, in part, by a novel ncRNA which promotes loss of NSC identity and maturation.
产前乙醇暴露可导致神经干细胞（NSCs）丢失和脑生长减少。在这里，我们评估了一种与 NSC 自我更新因子 Oct4/Pou5f1 相关的非编码 RNA（ncRNA），该 RNA 来自小鼠 9 号染色体上的一个加工假基因座（mOct4pg9），是否会导致由于乙醇而导致 NSCs 丢失。体外培养的源自胎鼠皮质的 NSCs 可模拟胎脑早期神经发生环境，其表达的 mOct4pg9 ncRNA 水平明显高于亲本 Oct4/Pou5f1 mRNA。乙醇暴露增加了 mOct4pg9 ncRNA 的表达，但降低了 Oct4/Pou5f1 的表达。增益和失能分析表明，mOct4pg9 的过表达通常模拟了乙醇暴露的影响，导致神经成熟相关转录物的增殖和表达增加。此外，mOct4pg9 与 Ago2 相关，与 miRNA 相关，包括抗增殖的 miR-328-3p，其水平在 mOct4pg9 过表达后降低。最后，mOct4pg9 抑制了 Oct4/Pou5f1-3'UTR 依赖性蛋白翻译。与这些观察结果一致，单细胞转录组分析的数据表明，mOct4pg9 表达的祖细胞缺乏 Oct4/Pou5f1，但过度表达了增加有丝分裂的转录物，表明启动了过渡扩增。总的来说，这些数据表明，乙醇对大脑发育的抑制作用部分是由一种新型 ncRNA 解释的，该 ncRNA 促进了 NSC 特性和成熟的丧失。
