Post-transcriptional gene regulation in normal and diseased neurons

项目摘要 21三体（T21，a.k.a.唐氏综合症）是智力残疾的最常见遗传形式， 遗传了三个21号染色体（HSA 21）。T21的动物模型已经证明了 突触畸变的数量。越来越多的证据表明，3'非翻译区（3' UTR）的基因可能是一个重要的基因。 mRNA在神经元的mRNA代谢中起重要作用，包括mRNA的稳定性、翻译和表达。 本地化3 'UTR是microRNA（miRNAs）靶向或RNA结合的顺式元件的温床。 结合蛋白（RBPs）。miRNA和RBP都与棘发生、树突状分支、 和突触发生。有趣的是，由于交替切割和多聚腺苷酸化（阿帕），神经元3 'UTR 比其他类型的细胞长得多，在细胞中增加了另一层转录后基因调控。 神经元细胞然而，关于3 'UTR在T21的病因学中的作用以及阿帕是如何在T21中表达的， 在T21细胞的神经发生过程中的调节从未被探索过。本项目的目标是：1） 检查3 'UTR同种型在正常和T21细胞的神经发生期间如何表达;和2）3' UTR同种型在神经发生后如何表达。 在正常和T21神经元中，转录调节通过3 'UTR执行。

PROJECT SUMMARY Trisomy 21 (T21, a.k.a. Down syndrome) is the most common genetic form of intellectual disability, and is caused by inheriting three copies of chromosome 21 (HSA21). Animal models of T21 have demonstrated a number of synaptic aberrations. Accumulating evidence indicates that the 3' untranslated region (3'UTR) of mRNA plays important roles in mRNA metabolism in neurons, including mRNA stability, translation, and localization. The 3'UTR is a hotbed for cis elements targeted by microRNAs (miRNAs) or bound by RNA- binding proteins (RBPs). Both miRNAs and RBPs have been implicated in spinogenesis, dendritic arborization, and synaptogenesis. Interestingly, owing to alternative cleavage and polyadenylation (APA), neuronal 3'UTRs are much longer than those in other cell types, adding another layer of post-transcriptional gene regulation in neuronal cells. However, little is known about the role of 3'UTR in the etiology of T21, and how APA is regulated during neurogenesis of T21 cells has never been explored. The objectives of this project are to 1) examine how 3'UTR isoforms are expressed during neurogenesis of normal and T21 cells; and 2) how post- transcriptional regulation is executed via 3'UTRs in normal and T21 neurons.