Iwaya Chihiro, Yu Sunny, Iwata Junichi
Department of Diagnostic & Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
Center for Craniofacial Research, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA.
J Dev Biol. 2024 Jul 6;12(3):19. doi: 10.3390/jdb12030019.
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 (, , and for miR-338-5p; , , , and for miR-374c-5p; and , , , , and 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.
额鼻畸形是由发育过程中额鼻突生长失败引起的。尽管基因研究已经确定了对额鼻发育至关重要的基因，但在这个过程中这些基因是如何被调控的，在很大程度上仍然未知。在这里，我们表明，微小RNA（一种能够靶向其靶mRNA进行降解或使其表达沉默的短非编码RNA）在小鼠额鼻发育相关基因的调控中起关键作用。利用小鼠基因组信息学（MGI）数据库，我们精心挑选了总共25个与额鼻畸形相关的小鼠基因，包括额鼻发育不全、额鼻发育异常和眼距过窄。通过生物信息学分析预测了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微小RNA（miR-338-5p、miR-653-5p和miR-374c-5p）对神经嵴细胞系O9-1细胞增殖和靶基因调控的影响。这些微小RNA的过表达显著抑制了细胞增殖，并且与额鼻畸形相关的基因（miR-338-5p对应的 、 和 ；miR-374c-5p对应的 、 、 和 ；miR-653-5p对应的 、 、 、 和 ）被这些微小RNA以剂量依赖的方式直接调控。综上所述，我们的结果突出了miR-338-5p、miR-653-5p和miR-374c-5p作为与额鼻畸形发育相关的致病性微小RNA。
