Deiodinases in the Brain

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Deiodinases (DIO) are central to regulating thyroid hormone action in the brain because they control the tissue concentration of the active hormone triiodothyronine (T3). DIO2, the outer ring, 5’-deiodinase expressed in the brain, converts T4 to T3 and is active primarily in two glial cell types: astrocytes and tanycytes. Astrocytes produce all of brain T3 during the fetal period and a significant fraction in adults. T3 from astrocytes reaches other neural cells, mainly neurons, devoid of DIO2. The T3 produced in the tanycytes travels to hypothalamic nuclei to perform neuroendocrine functions. DIO2 is expressed in the human fetal brain’s neural stem cells, known as outer radial glia. The inner ring, 5-deiodinase DIO3, converts T4 and T3 to the inactive compounds reverse T3 (rT3) and 3,3’T2, respectively, a reaction equivalent to suppressing thyroid hormone action. Brain DIO3 is active mainly in neurons. Thyroid hormones regulate the gene expression and enzymatic activity of DIO2 and DIO3. When T4 concentrations rise, DIO2 activity falls, and when T4 goes down, DIO2 increases. T3 stimulates the DIO3 gene, and DIO3 activity increases when T3 increases. The combined actions of DIO2 and DIO3 exert a "homeostatic-like mechanism" to maintain locally appropriate bioactivity of thyroid hormone by providing individual brain cells with the optimal concentrations of T3 required at different stages of development. These mechanisms regulate thyroid hormone action with a timeline specific to different brain regions.