Is the Intrinsic Genomic Activity of Thyroxine Relevant In Vivo? Effects on Gene Expression in Primary Cerebrocortical and Neuroblastoma Cells

Background: The possibility that the intrinsic genomic activity of thyroxine (T4) is of physiological relevance has been frequently hypothesized. It might explain gene expression patterns in the brain found in type 2-deiodinase (Dio2)-deficient mice. These mice display normal expression of most thyroid hormone-dependent genes, despite decreased brain triiodothyronine (T3). Methods: The relative effects of T4 and T3 on gene expression were analyzed in mouse neuro-2a (N2a) cells stably expressing the thyroid hormone receptor a1, and in primary mouse cerebrocortical cells enriched in astrocytes or in neurons. Cortical cells were derived from Dio2-deficient mice to prevent conversion of T4 to T3. T4 and T3 were measured in the media at the beginning and end of incubation, and T4 and T3 antibodies were used to block T4 and T3 action. Results: In all cell types, T4 had intrinsic genomic activity. In N2a cells, T4 activity was higher on negative regulation (1/5th of T3 activity) than on positive regulation (1/40th of T3 activity). T4 activity on positive regulation was dependent on the cell context, and was higher in primary cells than in N2a cells. Conclusion: T4 has intrinsic genomic activity. Positive regulation depends on the cell context, and primary cells appear much more sensitive than neuroblastoma cells. In all cells, negative regulation is more sensitive to T4 than positive regulation. These properties may explain the mostly normal gene expression in the brain of Dio2-deficient mice.