An unliganded thyroid hormone receptor causes severe neurological dysfunction

Congenital hypothyroidism and the thyroid hormone (T-3) resistance syndrome are associated with severe central nervous system (CNS) dysfunction, Becau se thyroid hormones are thought to act principally by binding to their nucl ear receptors (TRs), it is unexplained why TR knock-out animals are reporte d to have normal CNS structure and function. To investigate this discrepanc y further, a T-3 binding mutation was introduced into the mouse TR-beta loc us by homologous recombination, Because of this T-3 binding defect, the mut ant TR constitutively interacts with corepressor proteins and mimics the hy pothyroid state, regardless of the circulating thyroid hormone concentratio ns. Severe abnormalities in cerebellar development and function and abnorma l hippocampal gene expression and learning were found, These findings demon strate the specific and deleterious action of unliganded TR in the brain an d suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.