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J. Biol. Chem., Vol. 279, Issue 25, 26555-26562, June 18, 2004

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Induction of Larval Tissue Resorption in Xenopus laevis Tadpoles by the Thyroid Hormone Receptor Agonist GC-1^*

J. David Furlow, Ha Yung Yang, Mei Hsu¶, Wayland Lim||, Davy J. Ermio, Grazia Chiellini**, and Thomas S. Scanlan**

From the Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616-8519 and the ^**Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143-0446

A major challenge in understanding nuclear hormone receptor function is to determine how the same ligand can cause very different tissue-specific responses. Tissue specificity may result from the presence of more than one receptor subtype arising from multiple receptor genes or alternative splicing. Recently, high affinity analogs of nuclear receptor ligands have been synthesized that show subtype selectivity. These analogs can greatly facilitate the study of receptor subtype-specific functions in organisms where mutational analysis is problematic or where it is desirable for receptors to be expressed in their normal physiological contexts. We describe here the effects of the synthetic thyroid hormone analog GC-1 on the metamorphosis of the frog Xenopus laevis. The most potent natural thyroid hormone, 3,5,3'-triidothyronine or T3, shows similar binding affinity and transactivation dose-response curves for both thyroid hormone receptor isotypes, designated TR and TR. GC-1, however, binds to and activates TR at least an order of magnitude better than it does TR. GC-1 efficiently induces death and resorption of premetamorphic tadpole tissues such as the gills and the tail, two tissues that strongly induce thyroid hormone receptor during metamorphosis. GC-1 has less effect on the growth of adult tissues such as the hindlimbs, which express high TR levels. The effectiveness of GC-1 in inducing tail resorption and tail gene expression correlates with increasing TR levels. These results illustrate the utility of subtype selective ligands as probes of nuclear receptor function in vivo.

Received for publication, March 15, 2004

^* This work was supported by National Institutes of Health Grants DK-52798 (to T. S. S.) and DK-55511 (to J. D. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Present address: Dept. of Biochemistry, Dartmouth College, Hanover, NH 03755.

^|| Present address: St. Louis University School of Medicine, St. Louis, MO 63104.

To whom correspondence should be addressed: Section of Neurobiology, Physiology, and Behavior, University of California, 1 Shields Ave., Davis, CA 95616-8519. E-mail: jdfurlow{at}ucdavis.edu.

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