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MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid

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, inc...

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Autores principales: Yoshioka, Hiroki, Mikami, Yurie, Ramakrishnan, Sai Shankar, Suzuki, Akiko, Iwata, Junichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219963/
https://www.ncbi.nlm.nih.gov/pubmed/34178974
http://dx.doi.org/10.3389/fcell.2021.621045
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author Yoshioka, Hiroki
Mikami, Yurie
Ramakrishnan, Sai Shankar
Suzuki, Akiko
Iwata, Junichi
author_facet Yoshioka, Hiroki
Mikami, Yurie
Ramakrishnan, Sai Shankar
Suzuki, Akiko
Iwata, Junichi
author_sort Yoshioka, Hiroki
collection PubMed
description 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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spelling pubmed-82199632021-06-24 MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid Yoshioka, Hiroki Mikami, Yurie Ramakrishnan, Sai Shankar Suzuki, Akiko Iwata, Junichi Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2021-06-09 /pmc/articles/PMC8219963/ /pubmed/34178974 http://dx.doi.org/10.3389/fcell.2021.621045 Text en Copyright © 2021 Yoshioka, Mikami, Ramakrishnan, Suzuki and Iwata. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Yoshioka, Hiroki
Mikami, Yurie
Ramakrishnan, Sai Shankar
Suzuki, Akiko
Iwata, Junichi
MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid
title MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid
title_full MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid
title_fullStr MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid
title_full_unstemmed MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid
title_short MicroRNA-124-3p Plays a Crucial Role in Cleft Palate Induced by Retinoic Acid
title_sort microrna-124-3p plays a crucial role in cleft palate induced by retinoic acid
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219963/
https://www.ncbi.nlm.nih.gov/pubmed/34178974
http://dx.doi.org/10.3389/fcell.2021.621045
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