Hypothyroidism and brain developmental players
© Ahmed; licensee BioMed Central. 2015
Received: 19 November 2014
Accepted: 23 January 2015
Published: 11 February 2015
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.
Thyroid hormone (TH) is essential for a number of physiological processes and is particularly critical during nervous system development [1-7]. In developing brain THs stimulate and coordinate processes such as neuronal proliferation, migration, growth of axons and dendrites, synapse formation and myelination [4,7-22]. Disturbance of these processes leads to abnormalities in the neuronal network and may result in mental retardation and other neurological defects, including impaired motor skills and visual processing [23-27]. Hypothyroidism in adults has been associated with mood symptoms and reduced quality of life [16,28,29]. It is estimated that more than 12% of the US population will develop a thyroid condition during their lifetime, and an estimated 20 million Americans have already some form of thyroid disease . Besides, some of the most prominent and common symptoms of thyroid disease are those that result from the effects of TH on the CNS .
Types of thyroid hormones transporters and their iodothyronine derivates 
T3, T4, rT3, T2
T3, T4, rT3, T2, T4S, T3S, rT3S, T2S
T4, T3, rT3
T4, T3, T3S, T4S, rT3S
rT3, T4S, T3S, rT3S
T4, rT3, T3, T4S
T3, T4, rT3
T3, T4, rT3, T2
T4, T3, T4S, T3S
The importance of THTs for brain development was clearly demonstrated when researchers were able to link mutations in the human SLC16A2 gene coding for MCT8 to a previously described form of X-linked psychomotor retardation, the Allan-Herndon-Dudley syndrome [44,45]. All patients have a severe mental retardation, they cannot speak and most of them are unable to sit upright, crawl, stand or walk. Their thyroid phenotype is quite abnormal with a substantial decrease in plasma T4 and a more than twofold increase in plasma T3 as well as an increase in thyroid-stimulating hormone (TSH). Notably, preterm infants show transient hypothyroxinemia without TSH elevation . In addition, the degree of neurodevelopmental delay in preterm infants becomes severe according to the decreasing gestational age. Epidemiological and animal studies had shown that maternal subclinical hypothyroidism had significant negative impact on neurodevelopment [19,22,47]. To gain further insight in the pathogenic mechanisms underlying these diseases, MCT8 knockout (KO) mice have been generated [42,48]. The serum TH parameters in MCT8 KO mice are affected in the same way as in human patients but surprisingly they seem to develop normally, without overt neurological phenotype. Further analysis showed that the entry of T4 into the brain was not disturbed while uptake of T3 was diminished; suggesting that MCT8 is very important for T3 transport across the BBB and/or BCSFB while the passage of T4 is facilitated by other transporters . The overall T4 and T3 content of cerebrum and cerebellum were decreased by more than 50%, but detailed morphological studies as well as analysis of T3 target genes showed that neuronal uptake of T3 was impaired in an area- or even cell-specific manner. There were signs of a pronounced hypothyroid status in the thyroid-releasing hormone (TRH) producing neurons of the hypothalamic paraventricular nucleus, a mild hypothyroid status in RC3 expressing neurons of the striatum but an apparently normal thyroid status in several cell types in the cerebellum . It was concluded that in mice, more than in humans, other THTs can compensate for the lack of MCT8 in neurons, thereby protecting the brain from severe neurological deficits. The critical restriction to T3 transport in the absence of MCT8 could be located at the BBB rather than the plasma membrane of individual neurons . This agrees with the hypothesis that the high OATP1C1 expression in cerebral microvessels in rodents, as opposed to the situation in humans, contributes to the mild phenotype in MCT8 null mice . Recently also a combined MCT8- and D2-deficient mouse has been described. Analysis of 34 target genes in the cerebral cortex of single and double KO mice demonstrated that the expression of only 3 of them was affected by the elimination of MCT8 alone while this number increased to 24 when both MCT8 and D2 were absent, suggesting that D2 can partly compensate for the decrease in TH uptake in MCT8 deficient mice . While several groups have studied the exact localization of THTs at the level of the BCSFB in the choroid plexus and at the level of the BBB in both macro- and microvessels [51,53], only a few detailed reports are available on their cell-specific distribution in other regions of the brain. In situ hybridization (ISH) for MCT8 in murine brain showed the highest signal in several layers of the cerebral cortex and the hippocampus, in the amygdala, and many basal ganglia. In the cerebellum, expression was predominantly in the Purkinje cell layer. Using specific markers it could be shown that MCT8 is predominantly expressed in neurons, and to some extent in the tanycytes lining the third ventricle [50,54,55]. Analysis of primary murine cell cultures demonstrated high levels of MCT8 protein in neurons and low levels in astrocytes and oligodendrocytes. Importantly, MCT8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of TH supply to the brain during adulthood . Also, Müller et al.  indicated that MCT10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for MCT8 deficiency. LAT1 showed the same expression pattern as MCT8 . MCT8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of TH supply to the brain during adulthood . In human late fetal brain LAT2 was found only in microglia while in perinatal mice it was also widely expressed in neurons and astrocytes [35,55]. Information on the ontogenetic changes in THT expression in mammalian brain is quite scarce, especially for early developmental stages. In birds, THTs have been studied first in quail in relation to their possible involvement in the regulation of photoperiodicity at the level of the hypothalamus. Four members of the OATP family were found in choroid plexus: OATP1A1, OATP1B1, OATP1C1, and OATP3A2. The ventro-lateral walls of the basal tuberal hypothalamus showed strong expression of OATP1C1 and weak expression of OATP1B1 . Analysis of chicken OATP1C1 substrate specificity in a cell culture system showed that the protein is a highly specific transporter for T4 (Km 6.8 nM) . While MCT8 mRNA levels increased gradually between embryonic day (E) 4 and E10, OATP1C1 expression showed a divergent pattern. The overviews presented here are consistent with the evolving view that the importance of THTs for proper brain development .
General characteristics of the iodothyronine deiodinases 
Reaction catalyzed (Deiodination)
5 or 5' (ORD+IRD)
T4-T3, rT3- T2
- T4- rT3, T3- T2
- T4- rT3- T2
5: T4S>T3S>>T3, T4
5': rT3, rT3S>T2S>>T4
Sulfation of substrates
Substrate limiting KM
In vitro cofactor limiting KM
1–10 Mm DTT
>10 mM DTT
=70 mM DTT
Molecular mass (kDa)
- Liver, kidney, thyroid and pituitary.
- Pituitary, brain, BAT, thyroida, hearta and skeletal musclea.
- Brain, skin, uterus, placenta, fetus and in other sites of the maternal- fetal interface, such as the umbilical arteries and veins.
- Liver: endoplasmic reticulum. - kidney: basolateral plasma membrane
- Microsomal membranes
- Microsomal membranes
- Production serum T3 and the clearance of serum rT3.
- Catalyzes the outer ring deiodination of T4 to T3 and is thus important for the local production of T3.
- Catalyzes the inner ring deiodination of T4 to rT3 and of T3 to 3,3'-T2.
Activity in hypothyroidism
- Decrease in liver and kidney.
- Increase in all tissues.
- Decrease in brain.
- Increase in thyroid.
- No change
- No change
Active site residues
- Selenocysteine histidine and phenylalanine.
Human gene structure and location
- 1p32-p33, 17.5 kb and 4 exons.
- 14q24.3, 2 exons and 7.4-kb intron.
- TRE, RXR, no CAAT or TATA box.
Iopanoic acid inhibitor
General summary about the developmental thyroid hormone mechanisms (deiodinases, transporters, sulfotransferases and receptors) in human, rat and chicken 
Week post conception
Day post conception
- D3 is detected in uterine wall.
D2 and D3 are observed in uterine wall.
5 h (blastula stage)
- TRα mRNA is noticed and the levels markedly increased during neurulation.
- Thyroid gland begins.
7 -8.5 GD
- Time of implantation process.
- mRNA levels of D1, D2, and D3 are detected in whole embryos.
- Very high D3 activity is detected in decidual tissue.
- TBG is observed in thyroid follicle cells at GD 29.
- Thyroid gland is first visible as an endodermal thickening in the primitive buccal cavity.
- OATP1C1 expression appears.
- TRH is detected in fetal whole-brain at 4.5 weeks of gestation.
- TH is detected in rat embryotrophoblasts
- T4 is transferred via the placenta and has been found in the gestational fluid sac from 4 to 6 W.
- Maternal-embryo transfer of THs has been detected in embryonic coelomic fluid and amniotic fluid.
- All the mRNAs encoding THTs are expressed in placenta from 6 W and throughout pregnancy.
- T4, T3 and rT3 are detected in coelomic/amniotic fluids.
- T4, T3 and TRβ are detected in embryo/trophoblast unit.
- T3, THTs, Ds and TRs are expressed in whole embryos.
- TRs, D2 and D3 are noticed in fetal brain.
- TSH is first detected in the fetal pituitary.
- OATP1C1 expression is more than 10-fold higher in the telencephalon and diencephalon compared to the mesencephalon and rhombencephalon.
- D2 mRNA levels are highest in the diencephalon.
- The fetus is able to produce THs during this period, but prior to that time, is totally dependent on maternal THs.
- TRα mRNA is widely distributed in fore-, mid- and hind-brain.
- TBG levels are detected in fetal serum and increased through gestation.
- T4 and T3 are detected in embryonic brain.
- TRH is detected in fetal hypothalamus.
- D2 activity is observed in the brain before the onset of thyroid function and increases significantly.
- T4 and T3 are observed in serum and brain.
- Placental circulation established.
- D2 mRNA is noticed in cell clusters throughout the brain, particularly in rhombencephalon.
- Total serum T4 and T3 are low, free T4 is relatively high.
- TRs and TH are observed in fetal brain.
- OATP1C1 levels are declined substantially in all brain regions.
- rT3 is noticed in serum relatively high.
- D3 and D2 are detected in uterus and placenta.
- TH synthesis begins in fetal thyroid.
- Decreased mRNA expression of OATP1A2 but no change for OATP4A1 at 9–12 W compared to term.
- Expressions of mRNAs encoding MCT8, MCT10, OATP1A2 and
- TRH mRNA is detected in neurons of the fetal hypothalamus.
- D3 mRNA levels are markedly different in the telencephalon and diencephalon but remain stable, while the levels in mesencephalon and rhombencephalon show a sharp decrease and increase, respectively, during these days.
LAT1 are significantly lower prior to 14 W compared to term
- Pituitary TSH mRNA expression begins.
- Several elements of the TH action cascade are observed in the brain of embryos long before their own thyroid gland starts hormone secretion.
- TRH mRNA is detected in the developing paraventricular nuclei of the hypothalamus.
- D3 is observed in placenta and fetal epithelial cells.
- TRs are observed in liver, heart and lung.
- The thyroid gland is fully functional.
- D3 and TRs are detected in fetal liver.
- D1 and D2 are noticed in fetal tissues.
- D1 is noticed in heart and lung.
- TRH is produced in low levels in hypothalamus and increases approximately threefold by GDI9.5.
- Significant fetal TH secretion begins.
- Duplication of TBG concentrations.
- TH synthesis begins in fetal thyroid
- Brain D2 is elevated at the peak of neuroblast proliferation.
- TSH protein and Sulfotransferase are observed.
18 -22 GD
- The total T4 and T3 concentrations in fetuses are increased dramatically because of maturation of hormone synthesis of the fetal thyroid gland.
- The strong increase in intracellular T3 has been observed.
- The coordination between THTs and Ds is regulated both transplacental TH passage from mother to fetus and the development of the placenta itself through the progress of gestation.
- A steady increase in serum TH levels begins and continues to term.
- Significant fetal TH secretion begins.
- Plasma T4 levels start rising markedly around this day.
- Marked rise in serum TH but levels at birth still below those in adult.
- Serum total and free T4 and T3 near and below adult levels, respectively.
- Birth state.
- The decrease in DI activity in gonads is combined with the relatively high D3 activity.
- Thyroid system is less developed.
- The HPT axis begins to mature during the second half of gestation.
- As much as 17.5% of THs found in the newborn are of maternal origin.
- A significant increase in T3 production and in D2-activity and -mRNA expression are combined with a decreased in D3 activity.
- LAT1 and OATP4A1 have been localized only during the third trimester.
- Birth state.
- Brain development equivalent to human birth.
- Brain D2 activity is moderately elevated, whereas D3 activity and mRNA expression are highest between these days, followed by a dramatic decrease thereafter.
- Complete maturation of thyroid system.
- MCT8 has been localized in the placenta in all three trimesters of pregnancy.
- High concentrations of the different iodothyronine sulfates, T4S, T3S, rT3S and T2S, have been documented in human fetal and neonatal plasma as well as in amniotic fluid during the pregnancy.
- Serum TH levels continue to rise and are higher than adult levels between these days.
- D1 and D3 are expressed in the granule cells, whereas D2 is found mostly in the molecular layer and the Purkinje cells at that time.
- The levels of pituitary and serum TSH slowly decrease from PND 14–16 until reaching adult levels at PND 40.
- The increase in brain T3 production correlates with the appearance of TRβ expression in the cerebellum, telencephalon and optic lobes.
- TRH levels increase to adult levels by PNDI7–29, then decrease transiently between PND 31–41; adult levels are once again reached at PND 50.
E20 (at the moment of pipping)
- The brain is quite well developed at the time of hatching.
- Adult TRH mRNA expression patterns are observed at PND 22.
- The gradual increases in plasma T4 and hepatic D1 are detected.
- D3 levels are decreased in spleen and increased in skin and the lungs towards hatching.
- T3 production seems to be elevated markedly in liver.
- The rise of T4 is much more pronounced than in plasma.
- Diminished T4 sulfation is detected.
Complete maturation of thyroid gland.
- The T3 breakdown capacity by D3 is high in liver but low in kidney.
- T4 levels in plasma increase gradually during these days.
- In contrast to TRα expression which increases gradually towards hatching, expression of TRβ shows an abrupt elevation in late development, especially in the cerebellum.
- The majority of tissues express D3 together with either D1 or D2.
- The levels of D3 activity noticed in liver are rapidly drop by more than 90%.
- D1 levels in testis and ovary strongly decrease around hatching.
- Brain D2 activity is moderately decreased, whereas D3 activity is low.
- The low T3/T4 ratio is associated with high T3 breakdown in liver and with high T4 inactivation or T3 secretion in kidney.
- D1 activity gradually increases, reaching a maximum around these period, and decreases slowly to posthatch levels thereafter.
C1 (first day posthatch)
- The expression of D1 is limited to the mature granule cells and that of D3 to the Purkinje cells exclusively, whereas D2 remains clearly noticed in the molecular layer.
- Highest D1-activities and -mRNA expressions are detected in the liver, kidney, and intestine.
- The circulating T3/T4 ratio started to increase gradually during the first week after hatching.
This work was supported by a National Grant from the Research Center, Beni-Suef University, Beni-Suef city, Egypt.
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