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This version published online on August 21, 2003
Endocrinology, doi:10.1210/en.2003-0633
A more recent version of this article appeared on December 1, 2003
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Submitted on May 22, 2003
Accepted on August 8, 2003

Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the brain

Jimena Manzano1, Beatriz Morte1, Thomas S. Scanlan1, and Juan Bernal1*

1 Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Madrid, Spain. Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-2280, USA

* To whom correspondence should be addressed. E-mail: jbernal{at}iib.uam.es.

The availability of synthetic thyroid hormone receptor agonists provides a valuable tool to analyze whether specific receptor isoforms mediate specific physiological responses to thyroid hormone. GC-1 is a thyroid hormone analog displaying selectivity for thyroid hormone receptor {beta}. We have analyzed the effect of GC-1 on expression of thyroid hormone target genes in the cerebrum and cerebellum. Congenitally hypothyroid rats were treated with equimolar single daily doses of either triiodothyronine or GC-1. Both compounds similarly induced PCP-2 in the cerebellum. Expression of RC3 and Rhes in the caudate, and hairless, NT-3, Reelin, and RevErBA{alpha} in the cerebellum was analyzed by in situ hybridization on postnatal day 16. Hypothyroidism strongly decreased expression of RC3 and Rhes in the caudate, and hairless, RevErbA{alpha} and NT-3 in the cerebellum, and increased Reelin. Triiodothyronine treatment normalized the expression of all genes. However, GC-1 effectively normalized expression of Rhes and Reelin only. The lack of a GC-1 effect on most cerebellar genes can be explained by the known distribution of thyroid hormone receptor {alpha} and {beta} isoforms. However, in the caudate, RC3 and Rhes are expressed in the same cells and, therefore, they may represent specific gene responses linked to specific thyroid hormone receptor isoforms.
Key words: RC3 • Rhes • hairless • NT-3 • Reelin • RevErbA • cerebellum • Caudate






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