The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function

Abstract

Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and receptors is critical to ensure specific levels of TH action in neural cells. The type 3 iodothyronine deiodinase (DIO3) inactivates THs and is highly present in the developing and adult brain, where it limits their availability and action. DIO3 deficiency in mice results in a host of neurodevelopmental and behavioral abnormalities, demonstrating the deleterious effects of TH excess, and revealing the critical role of DIO3 in the regulation of TH action in the brain. The fact the Dio3 is an imprinted gene and that its allelic expression pattern varies across brain regions and during development introduces an additional level of control to deliver specific levels of hormone action in the central nervous system (CNS). The sensitive epigenetic nature of the mechanisms controlling the genomic imprinting of Dio3 renders brain TH action particularly susceptible to disruption due to exogenous treatments and environmental exposures, with potential implications for the etiology of human neurodevelopmental disorders.

Keywords: Dio3; Dlk1-Dio3 genomic imprinting; behavior; brain development; brain morphology; environmental factors; neuroendocrine function; sensory function; thyroid hormone; type 3 deiodinase.

Figure 1

Mechanisms of thyroid hormone action in the brain and its biological effects. DIO2 and DIO3, type 2, and type 3 deiodinase, respectively. T3, triiodothyroinine; T2, diiodothyronine; T4, thyroxine.

Figure 2

Neurological consequences of DIO3 deficiency in mice. The lack of DIO3 function prevents degradation of THs, increasing their availability and molecular action in the brain (red lines and arrows). Increased T3 action in the brain (grey arrow) leads to multiple neurological phenotypes (black arrows). TR, thyroid receptor; DIO2, type 2 deiodinase.

Figure 3

Genomic imprinting of Dio3 in the brain. (a) Simplified diagram of the mouse Dlk1-Dio3 imprinted domain showing the dominant pattern of allele-specific gene expression. An arbitrary number of pin point shapes indicate loci exhibiting allele-specific methylation (open circles, unmethylated; closed circles, methylated); (b) Brain variability in the percentage allelic contribution to Dio3 expression and associated IG-DMR methylation compared to fetal Dio3. Some brain regions exhibit relaxed or absent Dio3 imprinting despite unchanged IG-DMR methylation status [37]. (Data is approximate and based on parent-of-origin inheritance of the DIO3 mutation. Allelic contributions may add more than 100%, as the wild type allele may exhibit T3-dependent up-regulation upon loss of DIO3 function in the other allele).

Figure 4

Environmental factors and Dio3 imprinting. Environmental factors may influence Dio3 imprinting and expression, with consequences for TH action in the brain in affected (grey arrows) and future generations (dotted red arrow).