Differential effects of triiodothyronine and the thyroid hormone receptor beta-specific agonist GC-1 on thyroid hormone target genes in the b ain.
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 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-ErbAalpha 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-ErbAalpha, 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 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.
Manzano
Jimena
J
Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Madrid, Spain. jbernal@iib.uam.es.
Morte
Beatriz
B
Scanlan
Thomas S
TS
Bernal
Juan
J
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D002421:Caudate Nucleus / Q000502:physiology; D002531:Cerebellum / Q000502:physiology; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019579:Neocortex / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D051579:Neurogranin; D010636:Phenols / Q000494:pharmacology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D011988:Receptors, Thyroid Hormone / Q000819:agonists* / Q000235:genetics; D000091042:Reelin Protein; D037042:Thyroid Hormone Receptors beta; D013974:Thyroxine / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology*
D000085:Acetates; D002148:Calmodulin-Binding Proteins; C413355:GC 1 compound; D009419:Nerve Tissue Proteins; C496650:Nrgn protein, mouse; C496651:Nrgn protein, rat; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D000091042:Reelin Protein; C000717129:Reln protein, rat; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D051579:Neurogranin; C000717128:Reln protein, mouse; D019204:GTP-Binding Proteins; C442475:Rasd2 protein, rat; D013974:Thyroxine