TitleRetinoic acid-dependent regulation of miR-19 expression elicits vertebrate axis defects.
Publication TypeJournal Article
Year of Publication2013
AuthorsFranzosa, JA, Bugel, SM, Tal, TL, La Du, JK, Tilton, SC, Waters, KM, Tanguay, RL
JournalFASEB J
Volume27
Issue12
Pagination4866-76
Date Published2013 Dec
ISSN1530-6860
KeywordsAnimals, Body Patterning, Cytochrome P-450 Enzyme System, Gene Expression Regulation, Developmental, MicroRNAs, Retinoic Acid 4-Hydroxylase, Somites, Transcription, Genetic, Tretinoin, Zebrafish, Zebrafish Proteins
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.

DOI10.1096/fj.12-225524
Alternate JournalFASEB J.
PubMed ID23975936
PubMed Central IDPMC3834785
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
P42 ES016465 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States