Metabolism to a response pathway selective retinoid ligand during axial pattern formation.
We report identification of 9-cis-4-oxo-retinoic acid (9-cis-4-oxo-RA) as an in vivo retinoid metabolite in Xenopus embryos. 9-Cis-4-oxo-RA bound receptors (RARs) alpha, beta, and gamma as well as retinoid X receptors (RXRs) alpha, beta, and gamma in vitro. However, this retinoid displayed differential RXR activation depending on the response pathway used. Although it failed to activate RXRs in RXR homodimers, it activated RXRs and RARs synergistically in RAR-RXR heterodimers. 9-Cis-4-oxo-RA thus acted as a dimer-specific agonist. Considering that RAR-RXR heterodimers are major functional units involved in transducing retinoid signals during embryogenesis and that 9-cis-4-oxo-RA displayed high potency for modulating axial pattern formation in Xenopus, metabolism to 9-cis-4-oxo-RA may provide a mechanism to target retinoid action to this and other RAR-RXR heterodimer-mediated processes.
Pijnappel
W W
WW
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
Folkers
G E
GE
de Jonge
W J
WJ
Verdegem
P J
PJ
de Laat
S W
SW
Lugtenburg
J
J
Hendriks
H F
HF
van der Saag
P T
PT
Durston
A J
AJ
D000818:Animals; D019521:Body Patterning / Q000187:drug effects*; D019281:Dimerization; D018507:Gene Expression Regulation, Developmental; D007700:Kinetics; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology*; D000097768:Retinoic Acid Receptor gamma
D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma; C082925:retinoic acid receptor beta