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Differential Effects of Triiodothyronine and the Thyroid Hormone Receptor ß-Specific Agonist GC-1 on Thyroid Hormone Target Genes in the Brain

Instituto de Investigaciones Biomédicas Alberto Sols (J.M., B.M., J.B.), Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Madrid, Spain, and the Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology (T.S.), University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain. 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 ß. 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 single daily doses of either T₃ or GC-1. Both compounds similarly induced Purkinje cell protein-2 (PCP-2) in the cerebellum. Expression of RC3 and Rhes in the caudate, and hairless, neurotrophin-3, Reelin, and Rev-ErbA in the cerebellum, was analyzed by in situ hybridization on postnatal d 16. Hypothyroidism strongly decreased expression of RC3 and Rhes in the caudate, and hairless, Rev-ErbA, and neurotrophin-3 in the cerebellum, and increased Reelin. T₃ 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 and ß 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.

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