An unliganded thyroid hormone receptor causes severe neurological dysfunction

Abstract

Congenital hypothyroidism and the thyroid hormone (T3) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a T3 binding mutation was introduced into the mouse TR-␤ locus by homologous recombination. Because of this T3 binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.

Transient expression of thyroid hormone nuclear receptor TRβ2 sets S opsin patterning during cone photoreceptor genesis

“…For TR␤ GS/GS , exon 3 is mutated by changing residues in the P-box region of the first Zn-finger that compromise DNA binding of both TR␤1 and TR␤2 (Shibusawa et al, 2003). For TR␤ ⌬337T/⌬337T , exon 7 is altered deleting T337 in the T3 ligand binding domain, affecting both TR␤1 and TR␤2 (Hashimoto et al, 2001). B: TR␤2 ϩ/ϩ wild-type retina.…”

“…The ⌬337T mutation affects both TR␤1 and TR␤2. Circulating levels of T3 and T4 are elevated because the negative feedback mechanisms in the hypothalamus and pituitary are defective, such that the animals mimic a hypothyroid state (Hashimoto et al, 2001). Nonetheless, the homozygous mutant TR␤2 Ϫ/Ϫ , TR␤ GS/GS , and TR␤ ⌬337T/⌬337T animals show no overt differences in weight or activity compared with wild-type animals.…”

“…Finally, a requirement for T3 ligand binding is shown by the TR␤ ⌬337T/⌬337T mutant, in which ligand binding is inhibited (Hashimoto et al, 2001). This observation rules out a role for the unliganded receptor with its potential to repress gene transcription.…”

“…The generation and characterization of the TR␤2 Ϫ/Ϫ knockout, the TR␤ GS/GS , and the TR␤ ⌬337T/⌬337T knockin mouse lines have been reported (Abel et al, 1999;Hashimoto et al, 2001;Shibusawa et al, 2003), respectively. Mice were genotyped by Southern blotting (TR␤ ⌬337T/⌬337T ) or PCR as described (Abel et al, 1999;Hashimoto et al, 2001;Shibusawa et al, 2003; see the legend to Fig. 5).…”

Thyroid hormone action during brain development: More questions than answers

“…A more complex picture emerged with the analysis of mouse mutants expressing dominant negative thyroid hormone receptors due to mutations in the T3 binding domain (TRbeta delta337T; TRalpha1R384C). While TRbeta delta337T mutant mice showed an impaired cerebellar Purkinje cell development (Hashimoto et al, 2001) Purkinje cell and granule development was only slightly retarded in TRalpha1R384C mutant mice (Venero et al, 2005). However, in none of these mutant animals can the individual functions of thyroid hormone receptors in a given cell type be assessed since implementation of the mutant form always occurred ubiquitously.…”