Retinoic acid‐dependent regulation of miR‐19 expression elicits vertebrate axis defects

Abstract

Retinoic acid (RA) is involved in multifarious and complex functions necessary for vertebrate development. RA signaling is reliant on strict enzymatic regulation of RA synthesis and metabolism. Improper spatiotemporal expression of RA during development can result in vertebrate axis defects. microRNAs (miRNAs) are also pivotal in orchestrating developmental processes. While mechanistic links between miRNAs and axial development are established, the role of miRNAs in regulating metabolic enzymes responsible for RA abundance during axis formation has yet to be elucidated. Our results uncovered a role of miR-19 family members in controlling RA metabolism through the regulation of CYP26A1 during vertebrate axis formation. Global miRNA expression profiling showed that developmental RA exposure suppressed the expression of miR-19 family members during zebrafish somitogenesis. A reporter assay confirmed that cyp26a1 is a bona fide target of miR-19 in vivo. Transient knockdown of miR-19 phenocopied axis defects caused by RA exposure. Exogenous miR-19 rescued the axis defects induced by RA exposure. Taken together, these results indicate that the teratogenic effects of RA exposure result, in part, from repression of miR-19 expression and subsequent misregulation of cyp26a1. This highlights a previously unidentified role of miR-19 in facilitating vertebrate axis development via regulation of RA signaling.

Integrated Analysis of mRNA- and miRNA-Seq in the Ovary of Rare Minnow Gobiocypris rarus in Response to 17α-Methyltestosterone

“…Among these, miR-19, miR-183, miR-203, miR-204, miR-205, and miR-96 were downregulated. It has been reported that retinoic acid and cyp26a1 are necessary only during the early stages of somatogenesis (Sirbu and Duester, 2006), wherein it represses the expression of miR-19 family members as the 3 UTR of cyp26a1 as a bona fide target of miR-19, which was identified using in vivo reporter analysis (Franzosa et al, 2013). The present study showed that the targeted genes of miR-19, fabp3 and tgfb1, were upregulated following MT exposure.…”

High-throughput characterization of chemical-associated embryonic behavioral changes predicts teratogenic outcomes

“…Importantly, with such a noninvasive, automated endpoint, perturbations of AOP-associated molecular targets could be assessed through morpholino knockdown and/or RNA rescue (Andreasen et al 2006 ; Franzosa et al 2013 ; Miller et al 2014 ; Reimers et al 2006 ; Tilton et al 2006 ; Tilton and Tanguay 2008 ). The scale of the results presented here, using an experimental design including high numbers of biological well-replicates, permits powerful enrichment analysis to confirm such molecular targets.…”

The zebrafish miR-125c is induced under hypoxic stress via hypoxia-inducible factor 1α and functions in cellular adaptations and embryogenesis

“…Apart from inducing cell cycle arrest, miR-125c overexpression in zebrafish embryos resulted in cell apoptosis in brain, eyes and tail, implying an essential role for miR-125c in normal embryogenesis. Recently, miRNAs have been confirmed to regulate zebrafish morphogenesis and differentiation [ 63 ], somitogenesis [ 64 ], heart [ 65 ] and neural development [ 66 ]. Both miR-125a and miR-125b play excellent roles in the zebrafish brain development [ 67 ], meanwhile miR-125b also regulates the zebrafish eye development [ 67 ].…”