PNNL

Abstract

Retinoic acid (RA) is involved in multifarious and complex functions necessary for proper vertebrate growth and development. RA is reliant on strict enzymatic regulation of its synthesis and tissue specific metabolism. Improper spatial and temporal expression of RA signaling during development can result in vertebrate body axis defects. microRNAs (miRNAs) are also pivotal in orchestrating developmental processes. While mechanistic links between miRNAs in early embryonic patterning 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 experimental results uncovered a new role of miR-19 family members in controlling RA degradation through the regulation of CYP26A1 expression during vertebrate axis formation. We conducted global miRNA expression profiling that revealed developmental RA exposure suppressed the expression of several miR-19 family members during the early stages of zebrafish somitogenesis. A physiological reporter assay was used to confirm that cyp26a1 is a bona fide target of miR-19 in vivo. Transient knockdown of miR-19 expression phenocopied the body axis defects observed following RA exposure. Furthermore, cyp26a1 expression during somitogenesis was increased in RA exposed embryos and miR-19 morphants. In gain-of-function studies, 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 the subsequent misregulation of cyp26a1. This highlights a previously unidentified role of miR-19 in facilitating normal vertebrate axis development through the regulation of the RA signaling pathway.