Journal
TOXICOLOGY LETTERS
Volume 341, Issue -, Pages 51-58Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2021.01.017
Keywords
atRA; Cleft palate; Meg3; MEPM; TGF-beta/Smad signaling pathway
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Funding
- Natural Science Foundation of China [81801547, 21577119]
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Treatment with all-trans retinoic acid (atRA) promotes the upregulation of Meg3 in mouse embryonic palate mesenchymal (MEPM) cells, leading to a suppression of cell proliferation potentially through interacting with Smad2 protein to inhibit Smad signaling.
Palatal mesenchymal cell proliferation is essential to the process of palatogenesis, and the proliferation of mouse embryonic palate mesenchymal (MEPM) cells is impacted by both all-trans retinoic acid (atRA) and the TGF-beta/Smad signaling pathway. The long non-coding RNA (lncRNA) MEG3 has been shown to activate TGF-beta/Smad signaling and to thereby regulate cell proliferation, differentiation, and related processes. Herein, we found that atRA treatment (100 mg/kg) promoted Meg3 upregulation in MEPM cells, and that such upregulation was linked to the suppression of MEPM cell proliferation in the context of secondary palate fusion on gestational day (GD) 13 and 14. Moreover, the demethylation of specific CpG sites within the lncRNA Meg3 promoter was detected in atRA-treated MEPM cells, likely explaining the observed upregulation of this lncRNA. Smad signaling was also suppressed by atRA treatment in these cells, and RNA immunoprecipitation analyses revealed that Smad2 can directly interact with Meg3 in MEPM cells following atRA treatment. Therefore, we propose a model wherein Meg3 is involved in the suppression of MEPM cell proliferation, functioning at least in part via interacting with the Smad2 protein and thereby suppressing Smad signaling in the context of atRA-induced cleft palate. (C) 2021 Published by Elsevier B.V.
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