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Fetal Neurodev
Fetal Neurodev
REVIEW
Abstract
The development of fetal thyroid function is dependent on such as the cerebral cortex at specific developmental stages.
the embryogenesis, differentiation, and maturation of the There are many known cell membrane thyroid hormone
thyroid gland. This is coupled with evolution of the transporters in fetal brain that play an essential role in
hypothalamic–pituitary–thyroid axis and thyroid hormone regulating thyroid hormone concentrations in key structures.
metabolism, resulting in the regulation of thyroid hormone They also provide the route for intracellular thyroid
action, production, and secretion. Throughout gestation hormone interaction with associated thyroid hormone
there is a steady supply of maternal thyroxine (T4) which has receptors, which activate their action. There is a growing
been observed in embryonic circulation as early as 4 weeks body of experimental evidence from rats and humans to
post-implantation. This is essential for normal early fetal suggest that even mild maternal hypothyroxinemia may lead
neurogenesis. Triiodothyronine concentrations remain very to abnormalities in fetal neurological development. Our
low during gestation due to metabolism via placental and review will focus on the ontogeny of thyroid hormone in
fetal deiodinase type 3. T4 concentrations are highly fetal development, with a focus on cell membrane
regulated to maintain low concentrations, essential for transporters and TR action in the brain.
protecting the fetus and reaching key neurological sites Journal of Endocrinology (2011) 209, 1–8
2007, Gyamfi et al. 2009). The molecular mechanisms by This emphasizes the need for maternal T4 levels to be
which thyroid hormones affect fetal neurological structures maintained to ensure normal fetal brain development. This
are still not well understood. This review will briefly discuss also explains why even minimally reduced maternal T4 levels
some current aspects of the role of thyroid hormones in fetal in early pregnancy can result in adverse outcomes to the
neurological development, focusing on TH transporters and offspring (Lavado-Autric et al. 2003, Auso et al. 2004).
receptor activation in the brain.
B
Neurological cretinism Myxedermatous cretinism
C
Striatum
Neocortex
Cochlea
Myelination
Synapse formation
Neuronal proliferation
0 5 10 15 20 25 30 35 40 1 2 3 4
Birth
Weeks Years
Figure 1 (A) The ontogeny of fetal thyroid function and expression of thyroid hormone receptors and deiodinase enzymes during gestation
and early years postnatal are demonstrated. (B) Critical time points during gestation that require thyroid hormone action for fetal
neurological development. Neurological abnormalities can be seen if maternal or fetal hypothyroidism is present during gestation. (C) Rodent
studies, where time-specific actions of thyroid hormones on precise neurological and auditory structures were observed. Adapted image from
Bernal (2007).
transporters (Lat1 and Lat2), and monocarboxylate transpor- Horn & Heuer 2010). The T4-binding protein, transthyretin,
ters 8 and 10 (MCT8 and MCT10) (Abe et al. 1998, Friesema produced in significant amounts by the choroid plexus, has
et al. 2001, 2003, 2008). For thyroid hormone to gain access been implicated in this transport, and transthyretin may be
to the brain during maturation, it must pass through many involved in delivery of CSF thyroid hormone to the brain
different cell types which express the various cell membrane (Patel et al. 2010). T4 transported to the brain via blood
transporters. For rodents, the preferred route of TH entry is circulation passes through endothelial cells and is taken up by
through the cerebral circulation and its blood–brain barrier, astrocytes, probably through the Oatp1c1 cell membrane
with some thyroid hormone entering the cerebrospinal transporter (Fig. 2; Hernandez et al. 2007). Within the
fluid (CSF) via the choroid plexus (Dratman et al. 1991, astrocyte, T4 is deionated via D2 to produce T3, which then
T4
Oatp1c1
Nucleus
T4
D2 T2
T3
D3
Astrocyte T3
T 3 TR
A
MCT8 mRN
in
Neuron Prote
Figure 2 T4 is transported to the brain thyroid hormone-binding proteins such as transthyretin (TTR), where T4 then
passes out through endothelial cells lining the blood vessels. T4 is rapidly transported through the cell membrane
transporter, Oatp1c1, located on the surface of astrocytes. T4 is then metabolized intracellularly by D2 to T3, where it
can then be transported out from astrocytes by an as yet unidentified cell membrane transporter. Within the brain
parenchyma, T3 is then promptly uptaked by neurons and oligodendrocytes via the MCT8 cell membrane transporter.
Within the cell, T3 can either translocate and bind to thyroid hormone receptors (TRs), resulting in thyroid hormone
action, or be metabolized via D3 to biologically inactive T2.
exits the cell possibly via MCT8 (yet to be elucidated) and is MCT8 expression, cell surface translocation, and specific
taken up via MCT8 by oligodendrocytes and neurons (Fig. 2; substrate transport deficits, consequently producing a
Heuer et al. 2005). complete loss-of-function phenotype in patients (Kinne
In humans, the lack of MCT8 leads to greater neurological et al. 2009). MCT8 may transport other molecules essential
damage than in rodents, suggesting that other but as yet for brain maturation and which could explain the difference
undefined transporters are present in rodents. Lat2 has been between human and rodent brain maturation in the presence
proposed as a candidate, which although expressed in of MCT8 transporter mutations.
developing rat brain is not present in human developing
neurons (Wirth et al. 2009). In humans, the absence of the
MCT8 transporter (the Allan–Herndon–Dudley syndrome) TR genes and activity
results in X-linked moderate to severe mental retardation and
muscle hypotonia and hypoplasia (Dumitrescu et al. 2004, There are two TR genes (THRA and THRB), which encode
Friesema et al. 2004, Schwartz et al. 2005). Raised serum T3 for the four isotypes of TR (TRa1, TRb1, TRb2, and
concentrations and low T4 levels are present, but TSH levels TRb3) (Bernal 2007). The four isotypes all bind to T3 and
are normal suggesting a role for MCT8 in pituitary thyroid DNA and drive intracellular thyroid hormone action. Several
hormone uptake (Friesema et al. 2006). Patients also display isoforms of the TR from alternate RNA splicing are also seen.
altered and delayed maturation of myelination (Namba et al. Two of these are the TRa2 (c-erbAa2) and truncated TRb3
2008). More than two dozen MCT8 gene mutations have (DTRb3), which are known as nonreceptor proteins (Bassett
been reported linked to the X-chromosome (Friesema et al. et al. 2003). TRa2 has a conserved DNA-binding region but
2010). Almost all are missense mutations resulting in reduced is unable to bind T3. Conversely, DTRb3 is able to bind T3
but not to DNA. The physiological role of these nonreceptor rhombencephalon (Bradley et al. 1992). It is believed that the
proteins is still unknown (Forrest & Vennstrom 2000, O’Shea TRs found in these regions mediate the biological effects of T3
& Williams 2002, Bernal 2007). that has been locally generated from transported maternal T4,
TRs mediate their actions following homodimerization early in gestation. Conversely, TRb isoforms are expressed
or heterodimerization with retinoic acid receptors (RXR), more postnatally within specific neuronal populations such as
which then bind to specific sequences known as thyroid hippocampal pyramidal and granule cells, paraventricular
response elements (TREs) in the regulatory regions of target hypothalamic neurons, and cerebellar Purkinje cells (Bradley
genes (Wagner et al. 1995, Feng et al. 1998). A multitude of et al. 1989, Horn & Heuer 2010). Studies in TRb KO mice
transcription factors are involved. Without the presence of have shown that these isoforms are predominant in mediating
T3, the unliganded receptor (aporeceptor) recruits corepres- thyroid hormone effects on the development of the vision and
sors, such as nuclear receptor corepressors (NCoR) or auditory systems (Jones et al. 2003).
silencing mediator for retinoic and thyroid receptor There is a growing body of evidence suggesting that
(SMRT) and histone deacetylases, which retain the chromatin deficiencies in TR may not lead to abnormal brain
in a compact repressed position (Bernal 2007). However, in development as seen in hypothyroidism, which suggests that
the presence of T3, the binding of the hormone to TR the lack of the ligand (T3) is more detrimental than being TR
initiates transcription by the release of corepressors deficient (Bernal 2007). This has been demonstrated by Bernal
and recruiting coactivators (steroid receptor coactivators 1, et al. in TRa1 KO mice, which have normal cerebellar
SRC-1), histone acetylases (CREB-binding protein, CBP; development, even though the mice were hypothyroid
p300; and mammalian homolog of the yeast transcriptional (Morte et al. 2002). Another interesting study has demon-
activator GCN5, pCAF), and other mediators, all of which strated that TRa1 deletion did not affect cerebellar granule cell
assist in the access of transcription apparatus to the promoter migration during development, which is now known to take
regions (Fig. 3; Bernal 2007, Cheng et al. 2010). place in the absence of both receptor and T3 (Yacubova &
Both TR genes, THRA and THRB, are found within the Komuro 2002). It has been postulated by Bernal et al. that this
brain. In adult rat brain, more than 70–80% of all TRs result could well demonstrate that in vivo thyroid hormones are
present are in the TRa1 isoform. The receptor proteins are permissive when the TR are present, releasing any blocking
predominantly found in the cerebrum and cerebellum function that TR may be regulating (Bernal 2007). In contrast,
(Ercan-Fang et al. 1996). It has been postulated that the the absence of ligand could lead to aberrant receptor signaling,
TRa1 isoform also plays an important role during fetal brain which has been demonstrated with hypothyroid wild-type
development, both in humans and in rodents. This is animals with cell migration defects. This phenomenon has also
evidenced by detection in fetal rat brain of mRNA E11.5 been demonstrated using pheochromocytoma PC12 cells.
in the neural tube and E12.5 in the diencephalon and ventral When exposed to nerve growth factors, these cells differentiate
into neurons. Specifically, T3 has no effect on this process;
A Repression however, exogenous unliganded TRa1 will block this process
Corepressors T3 unless T3 is added to the culture medium (Munoz et al. 1993).
(CoR)
This has led to the hypothesis that the aporeceptor has
Transcriptional some transcriptional activity that may play an as yet unreco-
RXR TR machinery
gnized role in developmental processes. This also poses the
possibility of the aporeceptor possibly repressing specific
TRE
gene expression until T3 becomes available to the cells in a
B Activation time-specific manner.
Further analysis into the role of TR and brain development
Coactivators
(CoA) has been studied using mouse mutants expressing dominant
T3 Transcriptional
negative TR, where DNA binding is conserved with reduced
RXR TR machinery or absent T3-binding capacity. In two different models of
TRb mutant mice, impaired cerebellar Purkinje cell
TRE development and maturation and motor deficits were
observed, with cerebellar morphology similar to that seen
Figure 3 Schematic representation of thyroid hormone receptor in hypothyroidism (Forrest & Vennstrom 2000). This also
(TR) action. (A) Without the presence of the T3 ligand, corepressors
confirms the dominant role of TRb isoforms within the
(CoR) (nuclear receptor corepressors (NCoR) or silencing mediator
for retinoic and thyroid receptor (SMRT)) and histone deacetylases Purkinje cells of the brain. In TRa mutant models where
are recruited by TR to prevent transcription and translation of target T3-binding affinity was reduced by almost tenfold, mice
genes is demonstrated. (B) A bound TR with T3 results in the showed significant growth retardation and cardiac abnorm-
recruitment of coactivators (CoA) (steroid receptor coactivators 1, alities, with the heterozygous strain also demonstrating similar
SRC-1) and histone acetylases (CREB-binding protein, CBP; p300;
and mammalian homolog of the yeast transcriptional activator cerebellar abnormalities seen in hypothyroidism (Tinnikov
GCN5, pCAF) as well as the release of CoR, resulting in changes in et al. 2002). These mice also displayed striking anxiety-related
expression of target genes is demonstrated. behavior as evidenced by time spent motionless and reduced
exploratory behavior compared to the wild-type controls Bassett JH, Harvey CB & Williams GR 2003 Mechanisms of thyroid
(Tinnikov et al. 2002). This evidence further strengthens the hormone receptor-specific nuclear and extra nuclear actions. Molecular and
Cellular Endocrinology 213 1–11. (doi:10.1016/j.mce.2003.10.033)
hypothesis that TR play roles in fetal brain development and Bernal J 2005 Thyroid hormones and brain development. Vitamins and
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maintaining adult brain function (Bernal 2007). Further Bernal J 2007 Thyroid hormone receptors in brain development and function.
insights into phenotypic differences between these mutant Nature Clinical Practice. Endocrinology & Metabolism 3 249–259. (doi:10.1038/
ncpendmet0424)
mice strains are of particular interest, with additional work now
Bradley DJ, Young WS III & Weinberger C 1989 Differential expression of
being conducted in generating cell-specific TR mutant alpha and beta thyroid hormone receptor genes in rat brain and pituitary.
models (Quignodon et al. 2007, Flamant & Quignodon 2010). PNAS 86 7250–7254. (doi:10.1073/pnas.86.18.7250)
TRs have also been observed within the cytosol, where Bradley DJ, Towle HC & Young WS III 1992 Spatial and temporal expression
they interact with p85, a regulatory subunit of phosphatidyl- of alpha- and beta-thyroid hormone receptor mRNAs, including the beta
2-subtype, in the developing mammalian nervous system. Journal of
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pathway, resulting in induction of nitric oxide synthesis in Burmeister LA, Pachucki J & St Germain DL 1997 Thyroid hormones inhibit
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further investigation into the complex roles that TR play in
Calvo R, Obregon MJ, Ruiz de Ona C, Escobar del Rey F & Morreale de
physiological and pathological processes. Escobar G 1990 Congenital hypothyroidism, as studied in rats. Crucial role
of maternal thyroxine but not of 3,5,3 0 -triiodothyronine in the protection
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Calvo RM, Jauniaux E, Gulbis B, Asuncion M, Gervy C, Contempre B &
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relevant free thyroxine concentrations during early phases of development.
Our understanding of the complex processes involved in Journal of Clinical Endocrinology and Metabolism 87 1768–1777. (doi:10.1210/
ensuring normal fetal development is increasing. Knowledge jc.87.4.1768)
Chan S, Kachilele S, McCabe CJ, Tannahill LA, Boelaert K, Gittoes NJ,
of the key relationships between thyroid hormone and brain Visser TJ, Franklyn JA & Kilby MD 2002 Early expression of thyroid
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cell membrane transporters have yet to be clarified. S0165-3806(02)00459-5)
Cheng SY, Leonard JL & Davis PJ 2010 Molecular aspects of thyroid hormone
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Declaration of interest endo-110-2-367)
Dratman MB, Crutchfield FL & Schoenhoff MB 1991 Transport of
iodothyronines from bloodstream to brain: contributions by blood:brain
The authors declare that there is no conflict of interest that could be perceived
and choroid plexus:cerebrospinal fluid barriers. Brain Research 554 229–236.
as prejudicing the impartiality of the research reported.
(doi:10.1016/0006-8993(91)90194-Z)
Dumitrescu AM, Liao XH, Best TB, Brockmann K & Refetoff S 2004 A
novel syndrome combining thyroid and neurological abnormalities is
Funding associated with mutations in a monocarboxylate transporter gene. American
Journal of Human Genetics 74 168–175. (doi:10.1086/380999)
This research did not receive any specific grant from any funding agency in the Ercan-Fang S, Schwartz HL & Oppenheimer JH 1996 Isoform-specific
public, commercial or not-for-profit sector. 3,5,3 0 -triiodothyronine receptor binding capacity and messenger ribonu-
cleic acid content in rat adenohypophysis: effect of thyroidal state and
comparison with extrapituitary tissues. Endocrinology 137 3228–3233.
(doi:10.1210/en.137.8.3228)
Feng W, Ribeiro RC, Wagner RL, Nguyen H, Apriletti JW, Fletterick RJ,
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