MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid.
MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid.
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DOI：
10.3389/fcell.2021.621045
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发表时间：
2021
影响因子：
5.5
通讯作者：
Iwata J
中科院分区：
文献类型：
--
作者：
Yoshioka H;Mikami Y;Ramakrishnan SS;Suzuki A;Iwata J
唇裂伴/不伴腭裂（CL/P）是人类最常见的先天性出生缺陷之一，显示出遗传和环境因素的复杂性[例如，母亲暴露于酒精、香烟和视黄酸（RA）]。最近的研究表明，表观遗传因子，包括microRNAs (miRs)，会受到各种环境因素的改变。在这项研究中，为了研究miRs是否以及如何参与过量摄入全反式RA （atRA）诱导的腭裂（CP），我们在小鼠胚胎腭间充质（MEPM）细胞和atRA处理的小鼠胚胎中评估了通过生物信息学分析选择的前10个候选miRs。其中，过表达miR-27a-3p、miR-27b-3p和miR-124-3p通过下调cp相关基因导致MEPM细胞增殖能力显著降低。值得注意的是，我们发现在体内和体外，过量的atRA上调了miR-124-3p的表达，但没有上调miR-27a-3p和miR-27b-3p的表达。重要的是，在atra处理的MEPM细胞和暴露于atra的小鼠胚胎中，miR-124-3p特异性抑制剂通过使靶基因表达正常化，恢复了减少的细胞增殖，从而挽救了小鼠的CP。综上所述，我们的研究结果表明，atRA通过诱导小鼠miR-124-3p导致CP。
Cleft lip with/without cleft palate (CL/P) is one of the most common congenital birth defects, showing the complexity of both genetic and environmental contributions [e.g., maternal exposure to alcohol, cigarette, and retinoic acid (RA)] in humans. Recent studies suggest that epigenetic factors, including microRNAs (miRs), are altered by various environmental factors. In this study, to investigate whether and how miRs are involved in cleft palate (CP) induced by excessive intake of all-trans RA (atRA), we evaluated top 10 candidate miRs, which were selected through our bioinformatic analyses, in mouse embryonic palatal mesenchymal (MEPM) cells as well as in mouse embryos treated with atRA. Among them, overexpression of miR-27a-3p, miR-27b-3p, and miR-124-3p resulted in the significant reduction of cell proliferation in MEPM cells through the downregulation of CP-associated genes. Notably, we found that excessive atRA upregulated the expression of miR-124-3p, but not of miR-27a-3p and miR-27b-3p, in both in vivo and in vitro. Importantly, treatment with a specific inhibitor for miR-124-3p restored decreased cell proliferation through the normalization of target gene expression in atRA-treated MEPM cells and atRA-exposed mouse embryos, resulting in the rescue of CP in mice. Taken together, our results indicate that atRA causes CP through the induction of miR-124-3p in mice.
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