The type 2 iodothyronine deiodinase is expressed primarily in glial cells in the neonatal rat brain

Abstract

Thyroid hormone plays an essential role in mammalian brain maturation and function, in large part by regulating the expression of specific neuronal genes. In this tissue, the type 2 deiodinase (D2) appears to be essential for providing adequate levels of the active thyroid hormone 3,5,3-triiodothyronine (T3) during the developmental period. We have studied the regional and cellular localization of D2 mRNA in the brain of 15-day-old neonatal rats. D2 is expressed in the cerebral cortex, olfactory bulb, hippocampus, caudate, thalamus, hypothalamus, and cerebellum and was absent from the white matter. At the cellular level, D2 is expressed predominantly, if not exclusively, in astrocytes and in the tanycytes lining the third ventricle and present in the median eminence. These results suggest a close metabolic coupling between subsets of glial cells and neurons, whereby thyroxine is taken up from the blood and͞or cerebrospinal f luid by astrocytes and tanycytes, is deiodinated to T3, and then is released for utilization by neurons.Thyroid hormone controls a number of metabolic and developmental processes and, in particular, is an essential factor for normal mammalian brain maturation (1). In humans and other species, thyroid deficiency during the perinatal period results in irreversible brain damage and mental retardation (1, 2). The effects of thyroid hormone result primarily from changes in gene expression mediated through the binding of the active compound 3,5,3Ј-triiodothyronine (T3) to specific nuclear receptors of the steroid-retinoic acid-thyroid hormone superfamily. Previous studies have demonstrated that T3 nuclear receptors are expressed in a complex temporal pattern in specific regions of the brain that include the cerebral cortex, hippocampus, striatum, cerebellum, and hypothalamus (3, 4). These receptors are found predominantly in neurons and oligodendrocytes (5-7), and a number of neuronal genes have been shown to be regulated by thyroid hormone during development (8, 9).The majority of T3 in the brain is produced locally within the central nervous system by the 5Ј-deiodination of thyroxine (T4) (10). The type 2 deiodinase (D2) appears to be of particular importance in catalyzing the conversion of T4 to T3 in the brain during fetal and early neonatal life (11)(12)(13). During this period in the rat, the expression of D2 activity in brain increases at the end of gestation and is highest at 15-20 days of postnatal life (14). This pattern of activity corresponds temporally to the period when the developing brain is most dependent on thyroid hormone and correlates with increasing brain T3 concentrations, which peak at 2 weeks of age (13).An important property of the D2 is that its activity is markedly increased by thyroid hormone deficiency (15). This enhanced D2 activity serves to maintain T3 production in the brain in the face of limiting amounts of the prohormone T4 (16). Brain T3 levels thus appear to be protected to a considerable extent by alterations in circulating thyroid hormone levels (12...

Thyroid hormone action during brain development: More questions than answers

“…Studies in animal models have revealed that approximately up to 80 % of the active thyroid hormone T3 is produced locally in the CNS (Crantz et al, 1982) suggesting a prominent role of the activating enzyme D2 which exclusively catalyses outer ring deiodination. In contrast to thyroid hormone receptors that are highly enriched in oligodendrocytes and neurons, D2 is predominantly found in astrocytes throughout the brain (Guadano-Ferraz et al, 1997). In the rat, D2 expression is first detectable at E16.5 and increases successively until postnatal day 15.…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…The concentration of the active hormone T3 in CNS is controlled by two local mechanisms: the uptake of circulating plasma T4 and T3 mediated by transporters located in the blood-brain barrier and the plasma membrane of neural cells, such as MCT8 or OATP1C1 (33) or local production of T3 through the D2-mediated deiodination of T4. The local activation of T4 at a tissue level is more important in providing T3 to the neurons than is plasma (17,34,35). 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.…”

“…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). A paracrine paradigm for T3 supply is thought to occur in the central nervous system: D2 is highly expressed in glial cells providing T3 for neurons, which have higher D3 than D2 activity (34). This paracrine response is present in vivo as well, since the systemic administration of LPS, which induces a rapid increase of D2 in the tanycytes of the mediobasal hypothalamus and a consequent suppression of TRH expression (38), is absent in D2KO mice (39).…”

Type II iodothyronine deiodinase protein in chicken choroid plexus: additional perspectives on T3 supply in the avian brain

“…Their results were in agreement with previously reported data on the mRNA distribution of rat D2. Guadaño-Ferraz et al (1997) reported in situ hybridization studies for D2 in neonatal rat brain. They found excessive D2 mRNA expression in different brain areas, but more importantly, mainly, if not exclusively, in glial cells.…”