Thyroid hormone transporters and deiodinases in the developing human hypothalamus (original) (raw)
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Transport, Metabolism, and Function of Thyroid Hormones in the Developing Mammalian Brain
Frontiers in Endocrinology, 2019
Ever since the discovery of thyroid hormone deficiency as the primary cause of cretinism in the second half of the 19th century, the crucial role of thyroid hormone (TH) signaling in embryonic brain development has been established. However, the biological understanding of TH function in brain formation is far from complete, despite advances in treating thyroid function deficiency disorders. The pleiotropic nature of TH action makes it difficult to identify and study discrete roles of TH in various aspect of embryogenesis, including neurogenesis and brain maturation. These challenges notwithstanding, enormous progress has been achieved in understanding TH production and its regulation, their conversions and routes of entry into the developing mammalian brain. The endocrine environment has to adjust when an embryo ceases to rely solely on maternal source of hormones as its own thyroid gland develops and starts to produce endogenous TH. A number of mechanisms are in place to secure the proper delivery and action of TH with placenta, blood-brain interface, and choroid plexus as barriers of entry that need to selectively transport and modify these hormones thus controlling their active levels. Additionally, target cells also possess mechanisms to import, modify and bind TH to further fine-tune their action. A complex picture of a tightly regulated network of transport proteins, modifying enzymes, and receptors has emerged from the past studies. TH have been implicated in multiple processes related to brain formation in mammals-neuronal progenitor proliferation, neuronal migration, functional maturation, and survival-with their exact roles changing over developmental time. Given the plethora of effects thyroid hormones exert on various cell types at different developmental periods, the precise spatiotemporal regulation of their action is of crucial importance. In this review we summarize the current knowledge about TH delivery, conversions, and function in the developing mammalian brain. We also discuss their potential role in vertebrate brain evolution and offer future directions for research aimed at elucidating TH signaling in nervous system development.
Thyroid Hormone Economy in the Perinatal Mouse Brain: Implications for Cerebral Cortex Development
Cerebral Cortex, 2017
Thyroid hormones (THs, T4 and the transcriptionally active hormone T3) play an essential role in neurodevelopment; however, the mechanisms underlying T3 brain delivery during mice fetal development are not well known. This work has explored the sources of brain T3 during mice fetal development using biochemical, anatomical, and molecular approaches. The findings revealed that during late gestation, a large amount of fetal brain T4 is of maternal origin. Also, in the developing mouse brain, fetal T3 content is regulated through the conversion of T4 into T3 by type-2 deiodinase (D2) activity, which is present from earlier prenatal stages. Additionally, D2 activity was found to be essential to mediate expression of T3-dependent genes in the cerebral cortex, and also necessary to generate the transient cerebral cortex hyperthyroidism present in mice lacking the TH transporter Monocarboxylate transporter 8. Notably, the gene encoding for D2 (Dio2) was mainly expressed at the bloodcerebrospinal fluid barrier (BCSFB). Overall, these data signify that T4 deiodinated by D2 may be the only source of T3 during neocortical development. We therefore propose that D2 activity at the BCSFB converts the T4 transported across the choroid plexus into T3, thus supplying the brain with active hormone to maintain TH homeostasis
Early expression of thyroid hormone deiodinases and receptors in human fetal cerebral cortex
Developmental Brain Research, 2002
Thyroid hormones are known to be important for optimal development of the human central nervous system. Classically, maternal thyroid hormones have not been thought to have a major role in defining central nervous system development. However, recent epidemiological evidence has indicated that subtle deficiencies in circulating maternal thyroid hormones in the first trimester of pregnancy are associated with adverse neurodevelopment. We have used real time PCR to quantitate the expression of mRNAs encoding the thyroid receptor isoforms (TR a1, a2, b1 and b2) and thyronine deiodinase subtypes (59-DI, 59-DII and 5-DIII) in human fetal cerebral cortex from the first and second trimesters of pregnancy. Deiodinase subtype activities have also been determined in these tissues and compared to 'normal' adult human cerebral cortex. Iodothyronine deiodinase mRNAs were expressed in human fetal cerebral cortex from 7 to 8 weeks of gestation. The expression of 59-DI mRNA was variable in fetal life but increased relative to adult cortex (P,0.05), whereas the activity of this enzyme was below the level of assay detection. 59-DII mRNA and activity in fetal cerebral cortex was detectable from as early as 7-8 weeks but not significantly different from that in adult life except at 15-16 weeks when mRNA expression increased (P,0.05). Fetal cortex 5-DIII mRNA expression was present from the early first trimester but less abundant than in adult tissue (P,0.01) and 5-DIII activity appeared greateter in fetal cortex (P,0.01) as compared to adults. Only TR a1 mRNA was more abundantly expressed in fetal cortex than adult tissues (P,0.01). In contrast, the TR isoforms (a2 and b1) were expressed significantly less than in adult tissues (P,0.05). Only 26% of fetal cerebral cortex samples expressed TRb1. There is evidence that the developing fetal brain, as early as the first trimester, expresses TRs and exhibits the mechanisms of pre-receptor control of thyroid hormone supply. come in childhood, despite the presence of euthyroidism in 4837. the early neonatal period .
Thyroid Hormone Availability and Action during Brain Development in Rodents
Frontiers in Cellular Neuroscience, 2017
Thyroid hormones (THs) play an essential role in the development of all vertebrates; in particular adequate TH content is crucial for proper neurodevelopment. TH availability and action in the brain are precisely regulated by several mechanisms, including the secretion of THs by the thyroid gland, the transport of THs to the brain and neural cells, THs activation and inactivation by the metabolic enzymes deiodinases and, in the fetus, transplacental passage of maternal THs. Although these mechanisms have been extensively studied in rats, in the last decade, models of genetically modified mice have been more frequently used to understand the role of the main proteins involved in TH signaling in health and disease. Despite this, there is little knowledge about the mechanisms underlying THs availability in the mouse brain. This mini-review article gathers information from findings in rats, and the latest findings in mice regarding the ontogeny of TH action and the sources of THs to the brain, with special focus on neurodevelopmental stages. Unraveling TH economy and action in the mouse brain may help to better understand the physiology and pathophysiology of TH signaling in brain and may contribute to addressing the neurological alterations due to hypo and hyperthyroidism and TH resistance syndromes.
Hypothyroidism and brain developmental players
Most of our knowledge on the mechanisms of thyroid hormone (TH) dependent brain development is based on clinical observations and animal studies of maternal/fetal hypothyroidism. THs play an essential role in brain development and hormone deficiency during critical phases in fetal life may lead to severe and permanent brain damage. Maternal hypothyroidism is considered the most common cause of fetal TH deficiency, but the problem may also arise in the fetus. In the case of congenital hypothyroidism due to defects in fetal thyroid gland development or hormone synthesis, clinical symptoms at birth are often mild as a result of compensatory maternal TH supply. TH transporters (THTs) and deiodinases (Ds) are important regulators of intracellular triiodothyronine (T3) availability and therefore contribute to the control of thyroid receptors (TRs)-dependent CNS development and early embryonic life. Defects in fetal THTs or Ds may have more impact on fetal brain since they can result in intracellular T3 deficiency despite sufficient maternal TH supply. One clear example is the recent discovery of mutations in the TH transporter (monocarboxylate transporter 8; MCT8) that could be linked to a syndrome of severe and non reversible psychomotor retardation. Even mild and transient changes in maternal TH levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Animal studies are needed to increase our understanding of the exact role of THTs and Ds in prenatal brain development.
Pediatric Research, 1988
We have studied the ontogenesis of 5'-deiodinase (5'D) activity in rat brain during fetal life, its capacity to respond to maternal or fetal hypothyroidism, and its regulation by maternal thyroid hormones. Type I1 5'D (5' D-11) activity increases 4-fold during the period studied (17 to 22 days of gestation), mainly between days 19 and 21. Fetal brain T4 concentrations increase in parallel with fetal plasma T4, whereas fetal brain T3 concentrations increase 18 times (days 17-21), six times more than would have been expected from the small increase in fetal plasma T3 levels. Maternal thyroidectomy did not affect 5'D-I1 activity or thyroid hormone concentrations in fetal brain (except brain T4 at 18 days of gestation). Fetal hypothyroidism, induced by giving a goitrogen (methimazole) to the mothers, depleted all fetal tissues studied, including the fetal thyroid, from thyroid hormones. By 19 days of gestation, the fetal brain was able to respond to hypothyroidism with a 3-to 5-fold increase in 5'D-I1 activity. Earlier onset of treatment with methimazole led to 2-to 3-fold increases in 5'D already at 17 and 18 days of gestation, showing that when fetal thyroid secretion starts the fetal brain 5'D-I1 is able to respond to hypothyroidism. Replacement of methimazole-treated mothers with physiological doses of T4, given by constant infusion, increased T4 and T3 concentrations in fetal brain, and inhibited fetal, as well as maternal, brain 5'D-I1 activity. But treatment of the mothers with T3 did not change T3 concentrations in the fetal brain, despite the increase in fetal plasma T3, and actually increased 5'D-I1 in fetal brain. Maternal cerebral 5'D-I1 was not inhibited by T3 treatment. Inverse relationships were found between the 5'D-I1 and thyroid hormone concentrations in the fetal brain. These correlations were not identical for fetuses from thyroidectomized and control mothers. In fetuses from thyroidectomized dams, brain 5'D-I1 is more sensitive to a decrease in brain T4 than in the progeny of control
The Journal of Clinical Endocrinology & Metabolism, 2004
Thyroid hormones are required for human brain development, but data on local regulation are limited. We describe the ontogenic changes in T 4 , T 3 , and rT 3 and in the activities of the types I, II, and III iodothyronine deiodinases (D1, D2, and D3) in different brain regions in normal fetuses (13-20 wk postmenstrual age) and premature infants (24-42 wk postmenstrual age). D1 activity was undetectable. The developmental changes in the concentrations of the iodothyronines and D2 and D3 activities showed spatial and temporal specificity but with divergence in the cerebral cortex and cerebellum. T 3 increased in the cortex between 13 and 20 wk to levels higher than adults, unexpected given the low circulating T 3. Considerable D2 activity was found in the cortex, which correlated positively with T 4 (r ؍ 0.65). Cortex D3 activity was very low, as was D3 activity in germinal eminence and choroid plexus. In contrast, cerebellar T 3 was very low and increased only after midgestation. Cerebellum D3 activities were the highest (64 fmol/min⅐mg) of the regions studied, decreasing after midgestation. Other regions with high D3 activities (midbrain, basal ganglia, brain stem, spinal cord, hippocampus) also had low T 3 until D3 started decreasing after midgestation. D3 was correlated with T 3 (r ؍ ؊0.682) and rT 3 /T 3 (r ؍ 0.812) and rT 3 /T 4 (r ؍ 0.889). Our data support the hypothesis that T 3 is required by the human cerebral cortex before midgestation, when mother is the only source of T 4. D2 and D3 play important roles in the local bioavailability of T 3. T 3 is produced from T 4 by D2, and D3 protects brain regions from excessive T 3 until differentiation is required.
Neuroscience, 2012
Maternal thyroid hormones (THs) are important in early brain development long before the onset of embryonic TH secretion, but information about the regulation of TH availability in the brain at these early stages is still limited. We therefore investigated in detail the mRNA distribution pattern of the TH activating type 2 and inactivating type 3 deiodinases (D2 and D3) and the TH transporters, organic anion transporting polypeptide 1c1 (Oatp1c1) and monocarboxylate transporter 8 (Mct8), in chicken embryonic brain as well as in retina and inner ear from day 3 to day 10 of development. Oatp1c1, Mct8 and D3 are expressed in the choroid plexus and its precursors allowing selective uptake of THs at the blood-cerebrospinal fluid-barrier with subsequent inactivation of excess hormone. In contrast, the developing bloodbrain-barrier does not express Oatp1c1 or Mct8 but appears to be a site for TH activation by D2. Expression of D3 in several sensory brain centers may serve as protection against premature TH action. Expression of D2 and Mct8 but not D3 in the developing pituitary gland allows accumulation of active THs even at early stages. Mct8 is widely expressed in gray matter throughout the brain. This is the first comprehensive study on the dynamic distribution pattern of TH-transporters and deiodinases at stages of embryonic brain development when only maternal THs are available. It provides the essential background for further research aimed at understanding early developmental processes depending on maternal THs. Ó .be (V. M. Darras).
Role of thyroid hormone during early brain development
European Journal of Endocrinology, 2004
The present comments are restricted to the role of maternal thyroid hormone on early brain development, and are based mostly on information presently available for the human fetal brain. It emphasizes that maternal hypothyroxinemia -defined as thyroxine (T4) concentrations that are low for the stage of pregnancy -is potentially damaging for neurodevelopment of the fetus throughout pregnancy, but especially so before midgestation, as the mother is then the only source of T4 for the developing brain. Despite a highly efficient uterine -placental 'barrier' to their transfer, very small amounts of T4 and triiodothyronine (T3) of maternal origin are present in the fetal compartment by 4 weeks after conception, with T4 increasing steadily thereafter. A major proportion of T4 in fetal fluids is not protein-bound: the 'free' T4 (FT4) available to fetal tissues is determined by the maternal serum T4, and reaches concentrations known to be of biological significance in adults. Despite very low T3 and 'free' T3 (FT3) in fetal fluids, the T3 generated locally from T4 in the cerebral cortex reaches adult concentrations by midgestation, and is partly bound to its nuclear receptor. Experimental results in the rat strongly support the conclusion that thyroid hormone is already required for normal corticogenesis very early in pregnancy. The first trimester surge of maternal FT4 is proposed as a biologically relevant event controlled by the conceptus to ensure its developing cerebral cortex is provided with the necessary amounts of substrate for the local generation of adequate amounts of T3 for binding to its nuclear receptor. Women unable to increase their production of T4 early in pregnancy would constitute a population at risk for neurological disabilities in their children. As mild-moderate iodine deficiency is still the most widespread cause of maternal hypothyroxinemia in Western societies, the birth of many children with learning disabilities may already be preventable by advising women to take iodine supplements as soon as pregnancy starts, or earlier if possible.
Thyroid Hormones in Brain Development and Function
2015
Thyroid hormones are essential for brain developat through specific time windows influencing neurogenesis, neuronal migration, neuronal and glial cell differentiation, myelination, and synaptogenesis. The actions of thyroid hormones are mostly due to interaction of the active hormone T3 with nuclear receptors and regulation of gene expression. T4 and T3 also perform non-genomic actions. The genomically active T3 in brain derives in part from the circulation, and in part is formed locally by 5’-deiodination of T4, mediated by Dio2 in the astrocytes, in proportions that depend on the developmental stage. T4 and T3 are degraded by Dio3 present in neurons. Entry of T4 and T3 in brain is facilitated by specific transmembrane transporters, mainly the monocarboxylate transporter 8 (Mct8) and the organic anion transporter polypeptide 1c1 (Oatp1c1). In rodents Mct8 facilitates the transfer of T4 and T3 through the blood-brain barrier (BBB). Oatp1c1 transports T4 through the BBB and into to t...