Dell'Orco Michela, Elyaderani Amir, Vannan Annika, Sekar Shobana, Powell Gregory, Liang Winnie S, Neisewander Janet L, Perrone-Bizzozero Nora I
Department of Neurosciences, University of New Mexico Health Science Center, University of New Mexico, Albuquerque, NM 87131, USA.
Neurogenomics Division, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ 85004, USA.
Biology (Basel). 2021 Sep 20;10(9):939. doi: 10.3390/biology10090939.
The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and mRNAs associated with the neuronal development and synaptic plasticity proteins LSAMP and MARK3. Additionally, several downregulated miRNAs form ceRNA networks with mRNAs and circRNAs from MEF2D, PIK3R3, PTRPM and other neuronal proteins. Together, our results indicate that HuD regulates ceRNA networks controlling the levels of mRNAs associated with neuronal differentiation and synaptic physiology.
RNA结合蛋白HuD（又名ELAVL4）参与神经元发育和突触可塑性机制，包括与成瘾相关的过程，如可卡因条件性位置偏爱（CPP）和食物奖赏。该蛋白研究最多的功能是mRNA稳定化；然而，我们最近发现HuD还调控神经元中环状RNA（circRNA）的水平。为了研究HuD在控制与物质使用相关的编码和非编码RNA网络中的作用，我们在HuD基因敲除（KO）小鼠的纹状体中鉴定出差异表达的mRNA、circRNA和miRNA集合。我们的研究结果表明，显著下调的mRNA在与细胞形态和行为相关的生物学途径中富集。此外，HuD的缺失改变了15种与觅药相关的miRNA的水平。利用这些数据集，我们预测大量上调的miRNA与circRNA和与神经元发育及突触可塑性蛋白LSAMP和MARK3相关的mRNA形成竞争性内源RNA（ceRNA）网络。此外，一些下调的miRNA与来自MEF2D、PIK3R3、PTRPM和其他神经元蛋白的mRNA和circRNA形成ceRNA网络。总之，我们的结果表明HuD调控ceRNA网络，控制与神经元分化和突触生理学相关的mRNA水平。
