Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, 28645 East HWY 34, Corvallis, OR 97333, USA.
FASEB J. 2012 Apr;26(4):1452-61. doi: 10.1096/fj.11-194464. Epub 2012 Jan 17.
microRNAs (miRNAs) have emerged as regulators of a broad spectrum of neurodevelopmental processes, including brain morphogenesis, neuronal differentiation, and survival. While the role of miRNAs in establishing and maintaining the developing nervous system is widely appreciated, the developmental neurobehavioral role of miRNAs has yet to be defined. Here we show that transient disruption of brain morphogenesis by ethanol exposure results in behavioral hyperactivity in larval zebrafish challenged with changes in lighting conditions. Aberrations in swimming activity persist in juveniles that were developmentally exposed to ethanol. During early neurogenesis, multiple gene expression profiling studies revealed widespread changes in mRNA and miRNA abundance in ethanol-exposed embryos. Consistent with a role for miRNAs in neurobehavioral development, target prediction analyses identified multiple miRNAs misexpressed in the ethanol-exposed cohorts that were also predicted to target inversely expressed transcripts known to influence brain morphogenesis. In vivo knockdown of miR-9/9* or miR-153c persistently phenocopied the effect of ethanol on larval and juvenile swimming behavior. Structural analyses performed on adults showed that repression of miR-153c during development impacts craniofacial skeletal development. Together, these data support an integral role for miRNAs in the establishment of vertebrate neurobehavioral and skeletal systems.
microRNAs (miRNAs) 已成为广泛的神经发育过程的调节因子，包括脑形态发生、神经元分化和存活。虽然 miRNA 在建立和维持发育中神经系统的作用已被广泛认识，但 miRNA 在发育神经行为中的作用尚未被定义。在这里，我们表明，乙醇暴露导致脑形态发生短暂中断，会导致幼虫斑马鱼在光照条件变化下表现出行为过度活跃。在发育过程中暴露于乙醇的幼鱼中，游泳活动的异常持续存在。在早期神经发生过程中，多项基因表达谱研究显示，暴露于乙醇的胚胎中 mRNA 和 miRNA 丰度广泛变化。与 miRNA 在神经行为发育中的作用一致，靶预测分析确定了多个在乙醇暴露组中异常表达的 miRNA，这些 miRNA 也被预测靶向已知影响脑形态发生的反向表达转录本。miR-9/9* 或 miR-153c 的体内敲低持续模拟了乙醇对幼鱼和幼鱼游泳行为的影响。对成年动物进行的结构分析表明，miR-153c 在发育过程中的抑制会影响颅面骨骼发育。总之，这些数据支持 miRNA 在建立脊椎动物神经行为和骨骼系统中的重要作用。
