The functions of the imprinted miR379-410 cluster during neuronal migration in the developing telencephalon

发育中端脑神经元迁移过程中印迹miR379-410簇的功能

• 批准号: 276730358
• 负责人: Privatdozentin Dr. Jennifer Winter, Ph.D.
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/276730358?language=en
• 关键词: functions; imprinted; miR379; 410; cluster

Neuronal migration disorders can cause severe malformations of the brain such as, in the worst case, lissencephaly with complete loss of gyrie. Children with lissencephaly are typically severely mentally retarded, among other symptoms. Whereas it was assumed in the past that neuronal migration disorders are irreversible and therefore the diseases caused by these disorders are incurable new studies using the mouse as model have shown that it is possible, in principle, to rescue neuronal migration disorders postnatally. It is essential to understand the molecular mechanisms that drive neuronal migration to be able to develop therapies for these disorders in the future.The microRNA (miRNA) cluster miR379-410 consists of 38 miRNAs that are co-expressed in the brain and regulate different aspects of neurogenesis. We have shown recently that three miRNAs of the cluster (miR-369-3p, -496, -543) regulate the expression of N-cadherin in an additive manner and that these miRNAs control neuronal migration in the developing neocortex, among other functions. Their co-expression prompted us to hypothesize that more miRNAs of that cluster than the ones we have studied regulate neuronal migration. A bioinformatic analysis of the predicted target genes of all miRNAs of the cluster revealed a significant enrichment for genes functionally related to neuronal migration for an additional eight miRNAs of the miR379-410 cluster. Moreover, according to the bioinformatic analysis each of the predicted target genes will likely be bound by several miR379-410 cluster miRNAs suggesting an additive or synergistic effect of regulation. Among those predicted target genes are several that are causative for the severe neuronal migration disorder lissencephaly, namely Doublecortin (Dcx), Lissencephaly 1 (Lis1 or Pafah1b1) and arista related homeobox (Arx). In this project we aim at characterizing which of the miR379-410 cluster miRNAs regulate neuronal migration, which genes these miRNAs target and which of these target genes are important effectors of miRNA function.

神经元迁移障碍可导致严重的脑畸形，例如，在最坏的情况下，无脑回完全丧失。患有无脑回畸形的儿童通常会出现严重的智力迟钝等症状。尽管过去认为神经元迁移障碍是不可逆的，因此由这些障碍引起的疾病是不可治愈的，但使用小鼠作为模型的新研究表明，原则上可以在出生后挽救神经元迁移障碍。microRNA（miRNA）簇miR 379 -410由38种在大脑中共表达的miRNA组成，它们调节神经发生的不同方面。我们最近发现，簇中的三种miRNAs（miR-369- 3 p，-496，-543）以相加的方式调节N-钙粘蛋白的表达，并且这些miRNAs控制发育中的新皮质中的神经元迁移，以及其他功能。它们的共同表达促使我们假设该簇中的miRNA比我们研究的那些更多地调节神经元迁移。对该簇的所有miRNA的预测靶基因的生物信息学分析显示，对于miR 379 -410簇的另外8个miRNA，与神经元迁移功能相关的基因显著富集。此外，根据生物信息学分析，每个预测的靶基因将可能被几个miR 379 -410簇miRNA结合，表明调节的加和或协同效应。在这些预测的靶基因中，有几个是导致严重神经元迁移障碍无脑畸形的原因，即双皮质素（Dcx），无脑畸形1（Lis 1或Pafah 1b 1）和Arista相关同源框（Arx）。在这个项目中，我们的目标是确定哪些miR 379 -410簇miRNAs调节神经元迁移，这些miRNAs靶向哪些基因，以及这些靶基因中哪些是miRNAs功能的重要效应子。