Rodriguez Amaya Sanz, Engel Tobias, Palfi Arpad, Farrar G Jane, Henshall David C, Jimenez-Mateos Eva M
Department of Physiology & Medical Physics, Royal College of Surgeons in IrelandDublin 2, Ireland.
Smurfit Institute of Genetics, School of Genetics and Microbiology and Trinity College Institute of Neuroscience, Trinity College DublinDublin 2, Ireland.
Int J Physiol Pathophysiol Pharmacol. 2017 Dec 25;9(6):178-187. eCollection 2017.
MicroRNAs are important determinants of gene expression via post-transcriptional control of the protein levels of their mRNA targets. MicroRNA-134 (miR-134) has emerged as an important brain-specific microRNA which has been implicated in the control of dendritic spine morphology, neuronal differentiation and apoptosis. Here we show that Tubby-like protein 1 (Tulp1) is a target of miR-134. Tulp1 protein showed a similar cellular distribution pattern in the hippocampus to miR-134 and displayed an inverse expression pattern in the mouse retina. Bioinformatics analyses identified a conserved miR-134 binding site in the 3' untranslated region of both mouse and human and luciferase reporter assays confirmed miR-134 targets Tulp1 in vitro. Induction of prolonged seizures in mice resulted in upregulation of miR-134 and downregulation of protein levels of Tulp1 which were reversed in animals injected with locked nucleic acid-modified antagomirs targeting miR-134. Finally, knockdown of Tulp1 in human neurons caused an increase in vulnerability to excitotoxicity. These data identify Tulp1/TULP1 as a novel target of miR-134, which may contribute to underlying pathomechanisms in epilepsy.
微小RNA是通过对其mRNA靶标的蛋白质水平进行转录后控制来决定基因表达的重要因素。微小RNA-134（miR-134）已成为一种重要的脑特异性微小RNA，它与树突棘形态、神经元分化和凋亡的控制有关。在这里，我们表明类Tubby蛋白1（Tulp1）是miR-134的一个靶标。Tulp1蛋白在海马体中的细胞分布模式与miR-134相似，并且在小鼠视网膜中呈现出相反的表达模式。生物信息学分析在小鼠和人类的3'非翻译区鉴定出一个保守的miR-134结合位点，荧光素酶报告基因检测证实miR-134在体外靶向Tulp1。小鼠长时间癫痫发作的诱导导致miR-134上调和Tulp1蛋白水平下调，而在注射了靶向miR-134的锁核酸修饰反义寡核苷酸的动物中这种情况得到逆转。最后，在人类神经元中敲低Tulp1会导致对兴奋性毒性的易感性增加。这些数据确定Tulp1/TULP1是miR-
