PDF(Pubmed)
Abstract：
Frontonasal malformations are caused by a failure in the growth of the frontonasal prominence during development. Although genetic studies have identified genes that are crucial for frontonasal development, it remains largely unknown how these genes are regulated during this process. Here, we show that microRNAs, which are short non-coding RNAs capable of targeting their target mRNAs for degradation or silencing their expression, play a crucial role in the regulation of genes related to frontonasal development in mice. Using the Mouse Genome Informatics (MGI) database, we curated a total of 25 mouse genes related to frontonasal malformations, including frontonasal hypoplasia, frontonasal dysplasia, and hypotelorism. MicroRNAs regulating the expression of these genes were predicted through bioinformatic analysis. We then experimentally evaluated the top three candidate miRNAs (miR-338-5p, miR-653-5p, and miR-374c-5p) for their effect on cell proliferation and target gene regulation in O9-1 cells, a neural crest cell line. Overexpression of these miRNAs significantly inhibited cell proliferation, and the genes related to frontonasal malformations (Alx1, Lrp2, and Sirt1 for miR-338-5p; Alx1, Cdc42, Sirt1, and Zic2 for miR-374c-5p; and Fgfr2, Pgap1, Rdh10, Sirt1, and Zic2 for miR-653-5p) were directly regulated by these miRNAs in a dose-dependent manner. Taken together, our results highlight miR-338-5p, miR-653-5p, and miR-374c-5p as pathogenic miRNAs related to the development of frontonasal malformations.
摘要：
前鼻突畸形是由于在发育过程中额鼻突的生长失败引起的。尽管遗传研究已经确定了对额鼻发育至关重要的基因，在这个过程中，这些基因是如何被调节的，目前还不清楚。这里,我们发现microRNAs,它们是短的非编码RNA，能够靶向它们的靶mRNA进行降解或沉默它们的表达，在小鼠额鼻发育相关基因的调控中起着至关重要的作用。使用鼠标基因组信息学（MGI）数据库，我们共收集了25个与额鼻畸形有关的小鼠基因，包括额鼻孔发育不全,额鼻孔发育不良,和高度主义。通过生物信息学分析预测调控这些基因表达的微小RNA。然后，我们通过实验评估了前三个候选miRNA（miR-338-5p，miR-653-5p,和miR-374c-5p）在O9-1细胞中对细胞增殖和靶基因调控的影响，神经嵴细胞系.这些miRNA的过表达显著抑制细胞增殖,和与额鼻部畸形相关的基因（miR-338-5p的Alx1，Lrp2和Sirt1；miR-374c-5p的Alx1，Cdc42，Sirt1和Zic2；以及miR-653-5p的Fgfr2，Pgap1，Rdh10，Sirt1和Zic2）直接受这些方式的剂量依赖性调节。一起来看,我们的结果突出了miR-338-5p，miR-653-5p,和miR-374c-5p作为与额鼻畸形发展相关的致病miRNA。
