9-cis-retinoic acid, a potent inducer of digit pattern duplications in the chick wing bud.
The effects of retinoids are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid-X-receptors (RXRs). The physiological ligand of the RARs is all-trans-retinoic acid whereas RXRs have high affinity for 9-cis-retinoic acid, a naturally occurring retinoid isomer. RXRs are broadly expressed in embryonic and adult tissues, and they are capable of forming homodimers as well as heterodimers with RARs and other nuclear hormone receptors. The role of 9-cis-retinoic acid in regulating the activity of RXR homodimers and RXR-containing heterodimers is poorly understood in vivo. To begin to explore the function of 9-cis-retinoic acid in morphogenesis, we have examined the activity of this isomer in the chick wing. Using reverse transcriptase polymerase chain reaction analyses, we show that RXR gamma is expressed in stage 20 wing buds. Similar to all-trans-retinoic acid, the 9-cis-isomer induces pattern duplications when locally applied to chick wing buds, but the 9-cis isomer is about 25 times more potent than the all-trans form. Furthermore, applied all-trans-retinoic acid is converted to the 9-cis isomer in the wing bud. The ratio of 9-cis to all-trans-retinoic acid established in the tissue is approximately 1:25. This quantitative agreement between the degree of conversion and the 25-fold higher efficacy of the 9-cis isomer, raises the possibility that, at least in part, the effects of all-trans-retinoic acid on the wing pattern result from a conversion to the 9-cis isomer.(ABSTRACT TRUNCATED AT 250 WORDS)
Thaller
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V. and M. McLean Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030.
Hofmann
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C
Eichele
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D000014:Abnormalities, Drug-Induced / Q000196:embryology / Q000209:etiology; D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000002:abnormalities / Q000196:embryology; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004627:Embryonic Induction; D007536:Isomerism; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects; D014921:Wings, Animal / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology*
D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin