Thyroid Hormone-Regulated Mouse Cerebral Cortex Genes Are Differentially Dependent on the Source of the Hormone: A Study in Monocarboxylate Transporter-8- and Deiodinase-2-Deficient Mice

Abstract

Thyroid hormones influence brain development through the control of gene expression. The concentration of the active hormone T(3) in the brain depends on T(3) transport through the blood-brain barrier, mediated in part by the monocarboxylate transporter 8 (Mct8/MCT8) and the activity of type 2 deiodinase (D2) generating T(3) from T(4). The relative roles of each of these pathways in the regulation of brain gene expression is not known. To shed light on this question, we analyzed thyroid hormone-dependent gene expression in the cerebral cortex of mice with inactivated Mct8 (Slc16a2) and Dio2 genes, alone or in combination. We used 34 target genes identified to be controlled by thyroid hormone in microarray comparisons of cerebral cortex from wild-type control and hypothyroid mice on postnatal d 21. Inactivation of the Mct8 gene (Mct8KO) was without effect on the expression of 31 of these genes. Normal gene expression in the absence of the transporter was mostly due to D2 activity because the combined disruption of Mct8 and Dio2 led to similar effects as hypothyroidism on the expression of 24 genes. Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it increased that of negatively regulated genes. We conclude that gene expression in the Mct8KO cerebral cortex is compensated in part by D2-dependent mechanisms. Intriguingly, positive or negative regulation of genes by thyroid hormone is sensitive to the source of T(3) because Dio2 inactivation selectively affects the expression of negatively regulated genes.

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…A gene expression study recently conducted in mice with no D2 or MCT8 (double KO mice), showed that MCT8 has little effect on the expression of multiple genes regulated by the thyroid hormone due to a compensatory increase in D2 activity in discrete areas of mouse cerebrum. On the other hand, Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it allowed the increased expression of genes negatively regulated by T3 (36). In contrast, in D3KO mice, despite normal or low serum thyroid hormone concentrations, the absence of D3 activity in the brain results in excessive T3 effects in multiple brain regions, causing altered neuronal function (37).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…In normal thyroids the natural 127 I isotope is found predominantly in the follicular lumina. The identification of lumina devoid of 127 I and/or the demonstration of significant amounts of 127 I in the cytoplasm of the epithelial cells or on the apical membrane indicates impairment of the iodination pathway.…”

“…In normal thyroids the natural 127 I isotope is found predominantly in the follicular lumina. The identification of lumina devoid of 127 I and/or the demonstration of significant amounts of 127 I in the cytoplasm of the epithelial cells or on the apical membrane indicates impairment of the iodination pathway. To define the ultrastructural distribution of iodide using SIMS, thyroid lobes are processed in a similar way as for electron microscopy, including fixation with glutaraldehyde and preparation of semithin sections (20).…”

“…(B) Ultrathin sections were prepared and stained with uranyl acetate and lead citrate and examined with an electron microscope Zeiss EM169 (Carl Zeiss, Oberkochen, Germany). (C) Ultrastructural distribution of 127 I by secondary ion mass spectrometry (SIMS) imaging. Semi-thin sections were prepared, and the ultrastructural distribution of the iodide natural isotope ( 127 I) was obtained through imaging by SIMS, using the NanoSIMS 50 system.…”

“…White areas correspond to iodine detection. 127 I is homogeneously distributed in the follicular lumina and in a few intracytoplasmic vesicles. Reproduced with permission from Senou et al (20).…”