title: Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid.
abstract: Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA) signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor αb1 (RARαb1), a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM) specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARαb2 or concurrent depletion of RARαb1 and RARαb2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARαb1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA.
authors.affiliation: The Heart Institute, Molecular Cardiovascular Biology and Developmental Biology Divisions, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Enrico
authors.initials: E
authors.lastname: D'Aniello
authors.forename: Ariel B
authors.initials: AB
authors.lastname: Rydeen
authors.forename: Jane L
authors.initials: JL
authors.lastname: Anderson
authors.forename: Amrita
authors.initials: A
authors.lastname: Mandal
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Waxman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000235:genetics*; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction; D064793:Teratogenesis / Q000235:genetics*; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins
chemical_list: D018168:Receptors, Retinoic Acid; D029961:Zebrafish Proteins; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; C000607085:cyp26a1 protein, zebrafish