Zebrafish retinoic acid receptors function as context-dependent transcriptional activators

Waxman, J.S., and Yelon, D.
Developmental Biology   352(1): 128-140 (Journal)
Registered Authors
Waxman, Joshua, Yelon, Deborah
Zebrafish, Retinoic acid receptors, Transcription
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental
  • Genes, Dominant/genetics
  • Genes, Reporter/genetics
  • HEK293 Cells
  • Herpes Simplex Virus Protein Vmw65/metabolism
  • Humans
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Receptors, Retinoic Acid/genetics
  • Receptors, Retinoic Acid/metabolism*
  • Recombinant Fusion Proteins/metabolism
  • Signal Transduction/genetics
  • Trans-Activators/metabolism*
  • Tretinoin/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
21276787 Full text @ Dev. Biol.
RA receptors (RARs) have been thought to function through a binary repressor-activator mechanism: in the absence of ligand, they function as transcriptional repressors, and, in the presence of ligand, they function as transcriptional activators. This prevailing model of RAR mechanism has been derived mostly from in vitro studies and has not been widely tested in developmental contexts. Here, we investigate whether zebrafish RARs function as transcriptional activators or repressors during early embryonic anterior-posterior patterning. Ectopic expression of wild-type zebrafish RARs does not disrupt embryonic patterning and does not sensitize embryos to RA treatment, indicating that RAR availability is not limiting in the embryo. In contrast, ectopic expression of hyperactive zebrafish RARs induces expression of a RA-responsive reporter transgene as well as ectopic expression of endogenous RA-responsive target genes. However, ectopic expression of dominant negative zebrafish RARs fails to induce embryonic phenotypes that are consistent with loss of RA signaling, despite their ability to function as transcriptional repressors in heterologous cell culture assays. Together, our studies suggest that zebrafish RAR function is context-dependent and that, during early patterning, zebrafish RARs function primarily as transcriptional activators and may only have minimal ability to act as transcriptional repressors. Thus, it seems that the binary model for RAR function does not apply to all in vivo scenarios. Taking into account studies of RA signaling in tunicates and tetrapods, we propose a parsimonious model of the evolution of RAR function during chordate anterior-posterior patterning.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes