title: Excessive feedback of Cyp26a1 promotes cell non-autonomous loss of retinoic acid signaling.
abstract: Teratogenic levels of retinoic acid (RA) signaling can cause seemingly contradictory phenotypes indicative of both increases and decreases of RA signaling. However, the mechanisms underlying these contradictory phenotypes are not completely understood. Here, we report that using a hyperactive RA receptor to enhance RA signaling in zebrafish embryos leads to defects associated with gain and loss of RA signaling. While the gain-of-function phenotypes arise from an initial increase in RA signaling, using genetic epistasis analysis we found that the loss-of-function phenotypes result from a clearing of embryonic RA that requires a rapid and dramatic increase in cyp26a1 expression. Thus, the sensitivity of cyp26a1 expression to increased RA signaling causes an overcompensation of negative feedback and loss of embryonic RA signaling. Additionally, we used blastula transplantation experiments to test if Cyp26a1, despite its cellular localization, can limit RA exposure to neighboring cells. We find that enhanced Cyp26a1 expression limits RA signaling in the local environment, thus providing the first direct evidence that Cyp26 enzymes can have cell non-autonomous consequences on RA levels within tissues. Therefore, our results provide novel insights into the teratogenic mechanisms of RA signaling and the cellular mechanisms by which Cyp26a1 expression can shape a RA gradient.
authors.affiliation: Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, USA; Molecular and Developmental Biology Graduate Program, University of Cincinnati Medical Center, Cincinnati, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Rydeen
authors.affiliation: Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, USA; Magistère Européen de Génétique, University Paris Diderot, Paris, France.
authors.forename: Norine
authors.initials: N
authors.lastname: Voisin
authors.affiliation: Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: D'Aniello
authors.affiliation: Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, USA.
authors.forename: Padmapriyadarshini
authors.initials: P
authors.lastname: Ravisankar
authors.affiliation: Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, USA; Magistère Européen de Génétique, University Paris Diderot, Paris, France.
authors.forename: Claire-Sophie
authors.initials: CS
authors.lastname: Devignes
authors.affiliation: Molecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children's Research Foundation, Cincinnati, USA. Electronic address: joshua.waxman@cchmc.org.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Waxman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D002452:Cell Count; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D025461:Feedback, Physiological; D007267:Injections; D032383:Myocytes, Cardiac / Q000166:cytology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism*; 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
keywords: Cyp26a1; Feedback; Retinoic acid; Teratogenesis; Zebrafish