Abstract
Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured mouse embryonic lip mesenchymal cells (MELM cells) and O9-1 cells, a mouse cranial neural crest cell line. In addition, we found that phenytoin, an inducer of CL, decreased cell proliferation through miR-196a-5p induction. Notably, treatment with a specific inhibitor for miR-196a-5p restored cell proliferation through normalization of expression of CL-associated genes in the cells treated with phenytoin. Taken together, our results suggest that phenytoin induces CL through miR-196a-5p induction, which suppresses the expression of CL-associated genes.
Highlights
Received: 14 January 2021Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations, with a prevalence of 1 in 500 to 1 in 2500 live births worldwide
To evaluate the role of the candidate miRNAs, primary Mouse Embryonic Lip Mesenchymal (MELM) cells were treated with a miRNA mimic for either miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, or miR-710, which were predicted through our bioinformatic analyses [45]
These results indicate that induction of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 can inhibit cell proliferation in lip mesenchymal cells, leading to cleft lip (CL)
Summary
Received: 14 January 2021Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations, with a prevalence of 1 in 500 to 1 in 2500 live births worldwide. There are syndromic and nonsyndromic forms of CL/P, often caused by gene mutations, teratogenic exposure, and chromosomal modifications [1,2,3,4]. Previous mouse genetic studies showed that mutations in various genes result in cleft lip (CL), cleft palate, and midfacial cleft. An increasing number of studies suggest that the causative factors for birth defects might be grouped according to shared functions (e.g., cell proliferation, differentiation) and pathways (e.g., growth factor signaling pathways). It remains unclear how epigenetic factors regulate
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