Thyroid Hormones and Brain Development

Thyroid Hormones and Brain Development

63 Thyroid Hormones and Brain Development J Bernal, Consejo Superior de Investigaciones Cientificas, and Center for Biomedical Research on Rare Diseas...

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63 Thyroid Hormones and Brain Development J Bernal, Consejo Superior de Investigaciones Cientificas, and Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain ß 2009 Elsevier Inc. All rights reserved.

Chapter Outline 63.1 63.2 63.2.1 63.2.2 63.2.3 63.2.4 63.3 63.3.1 63.3.2 63.3.2.1 63.3.2.2 63.3.3 63.3.3.1 63.3.3.2 63.4 63.4.1 63.4.2 63.4.3 63.5 63.6 63.6.1 63.6.2 63.6.3 63.6.4 63.6.5 63.6.6 63.6.7 63.6.8 63.7 63.7.1 63.7.2 63.7.3 63.7.4 63.7.5 63.7.6 63.8 References

Introduction An Overview of Brain Development and the Effects of Thyroid Hormone Action of Thyroid Hormones on Neurogenesis Action of Thyroid Hormones on Cell Migration Action of Thyroid Hormones on Myelination Other Structural Defects Caused by Hypothyroidism Thyroid Hormones in Brain Sources of Thyroid Hormone for the Fetus Expression and Regional Distribution of Deiodinases Type 2 deiodinase Type 3 deiodinase Transport of Thyroid Hormones to the Brain The brain barriers Thyroid hormone transporters Thyroid Hormone Action The Nuclear Pathway of Thyroid Hormone Action Modulation of Transcription by Nuclear Receptors for Thyroid Hormone Extragenomic Pathways of Thyroid Hormone Action Nuclear Thyroid Hormone Receptors in the Brain Mechanisms of Thyroid Hormone Action in the Brain Regulation of Brain Gene Expression by Thyroid Hormone Mechanisms of Action of Thyroid Hormones on Myelination Mitochondrial Actions of Thyroid Hormones Control of Cell Migration Control of Neural Cell Differentiation Regulation of the Expression of Genes Involved in Signaling Transcription Factors and Splicing Regulators Mechanisms of Gene Regulation by Thyroid Hormone Epidemiological and Clinical Aspects Iodine Deficiency Disorders – Endemic Cretinism Congenital Hypothyroidism Maternal Hypothyroidism and Maternal Hypothyroxinemia The Hypothyroxinemia of Prematurity Thyroid Hormone Transporter Mutations Triiodothyronine Receptor Mutations Conclusions and Perspectives

63.1 Introduction Thyroid hormone deficiency or excess, in adults, can lead to an extensive array of clinical manifestations ( Joffe and Sokolov, 1994; Laureno, 1996).

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Hypothyroidism causes lethargy, hyporeflexia, and poor motor coordination. Subclinical hypothyroidism is often associated with memory impairment. Bipolar affective disorders, depression, or loss of cognitive functions may be a manifestation of hypothyroidism, 2005

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especially in the elderly (Ganguli et al., 1996). Hyperthyroidism causes anxiety, irritability, and hyperreflexia. Psychobehavioral alterations such as mood disorders, dementia, confusion, personality changes, and psychosis can be a manifestation of either hypothyroidism or hyperthyroidism. Disorders of the central nervous system (CNS), due to an imbalance of thyroid hormone economy, in the adult are usually reversible with proper treatment, indicating that thyroid hormone alterations of adult onset do not leave permanent structural defects. During development, however, deficiency of thyroid hormones may cause irreversible damage, the consequences of which depend on the specific timing of onset and duration of thyroid hormone deficiency. The purpose of this chapter is to analyze the actions of thyroid hormones during brain maturation, and the clinical conditions associated with defective thyroid hormone signaling, in the light of developing concepts on thyroid hormone physiology and action. Several reviews on this topic have been published recently (Anderson et al., 2003; Bernal, 2005a, 2007; Koibuchi and Iwasaki, 2006; Morreale de Escobar et al., 2004).

63.2 An Overview of Brain Development and the Effects of Thyroid Hormone Most of our knowledge on thyroid hormone action in the brain derives from animal studies, especially the rat. Although the sequence of developmental events is similar among mammals, the timing of development in relation to birth presents substantial differences. (Fisher and Polk, 1988; Holt et al., 1981; Morreale de Escobar et al., 1983) In humans and rodents, most brain growth occurs after birth, although the rat is born with a less-developed thyroid axis than the human. As a useful reference ‘‘the newborn rat may be compared with a human fetus in the second trimester of pregnancy, and the newborn human baby to a 6–10 day old rat’’ (Legrand, 1984). The following is a brief description of the most important morphogenetic effects of thyroid hormones during brain development. The mechanisms by which thyroid hormones influence these processes are complex and not well defined, and will be discussed in the section dealing with the molecular actions of thyroid hormones. 63.2.1 Action of Thyroid Hormones on Neurogenesis There is no clear evidence that thyroid hormones are involved in the early events of neural development.

Rather, thyroid hormones are involved in late events, such as migration and terminal differentiation of neurons and glia. In the CNS, the progenitors are generated in the wall of the neural tube, the pseudostratified neuroepithelium, or ventricular zone. During the secondary stages of neurogenesis, another zone of proliferating cells is formed – the subventricular zone (SVZ) – located immediately below the ventricular zone. The SVZ expands during late gestation and early postnatal development. Secondary neurogenesis extends in rodents to the second postnatal week and in humans to the second year. The SVZ provides a large number of neurons during late stages of development, such as striatal neurons, granular cells of the hippocampus and the cerebellum, interneurons of the olfactory bulb, and glial cell precursors of oligodendrocytes and astrocytes (Zerlin et al., 1995). A role of thyroid hormones on proliferation of neural precursors in the embryonic neurogenic areas has not been demonstrated, but effects have been shown recently in adult animals. In the adult brain, neurogenesis occurs in two regions: the SVZ and the subgranular zone (SGZ). The SVZ, in adult rodents, generates olfactory bulb interneurons. The SGZ is adjacent to the granular layer of the dentate gyrus, and generates granular neurons destined to this layer. Interestingly, hypothyroidism depresses, and thyroid hormone stimulates, neurogenesis in these two areas (Ambrogini et al., 2005; Desouza et al., 2005; Lemkine et al., 2005; MonteroPedrazuela et al., 2006). 63.2.2 Action of Thyroid Hormones on Cell Migration Thyroid hormone exerts important influences on cell migration in the neocortex and the cerebellum. One of the mechanisms involved could be an action on the radial glia, one of the first differentiated cells generated in the neuroepithelium. The radial glia extends long processes to the cerebral wall, providing a scaffold that serves for cell migration in the cerebral cortex, hippocampus, and cerebellum (Hatten, 1990; Rakic, 1972). Later in development, the radial glia differentiates into astrocytes and ependymal cells (Gaiano et al., 2000). Radial glia maturation in the fetal rat brain is delayed in the hippocampus of hypothyroid rats (Martinez-Galan et al., 1997). The six layers of the cerebral cortex are formed by a process known as inside-out migration. In the neocortex, rapid proliferation of the neuroblasts leads to the formation of three layers: the ventricular zone containing proliferating cells, the intermediate zone

Thyroid Hormones and Brain Development

containing axons and migrating neurons, and the preplate containing postmitotic neuronal precursors. As arriving cells accumulate, they divide the preplate in two layers – the transient subplate and the marginal zone or future layer I (Marin-Padilla, 1978, 1983). Neuronal precursors accumulate between these layers and form the cortical plate, which progressively develops into layers II–VI of the mature cortex. These layers are formed by a process known as inside-out migration: the cells generated in the ventricular layer migrate along the radial glia to the edge of the most superficial layer, layer I, where they stop migrating. As new cells arrive, the cells that arrived earlier are displaced back. In this way, the first layer to form is layer VI (around embryonic day (E) 13 in the rat) and layer II is formed last (around E17). Layer I contains a special type of cells, the Cajal-Retzius neurons (Marin-Padilla, 1990), which are influenced by the thyroid hormone (Alvarez-Dolado et al., 1999b; Garcı´a-Ferna´ndez et al., 1997). These cells produce a large extracellular matrix protein known as Reelin (Meyer, 2007). Reelin is essential for the orderly migration and the establishment of neocortical layers and is under thyroid hormone control. Cajal-Retzius cells also have an important role in the migration of neuronal precursors in the hippocampus and in the establishment of synaptic connections (Del Rio et al., 1997). Deficiency of thyroid hormone during the period of cortical development leads to less-defined cortical layers, indicating disturbances of cell migration. This has been carefully shown by Berbel et al. (1993, 1994, 2001), with the demonstration that neurons originating at a certain time during cortex development were misplaced in hypothyroid rats, so that interhemispheric connections project to different layers of the contralateral cortex than in normal rats. This process is extremely sensitive to the lack of thyroid hormones, because induction of transient maternal hypothyroidism in pregnant rats at E12–E15 caused significant misplacement of cells in the neocortex and hippocampus of the offspring, when analyzed at 40 days of age, and audiogenic seizures (Auso´ et al., 2004). Even light thyroid hormone deficiency during pregnancy caused neuronal ectopias in the corpus callosum (Goodman and Gilbert, 2007). The cerebellum originates from the rhombencephalic neuroepithelium (Altman and Bayer, 1997; Hatten and Heintz, 1995, 1999). The dorsal part of the fourth ventricle is covered by the tela choroidea, a membrane which will form the choroid plexus. The upper border of the neuroepithelium, contiguous with the tela choroidea, forms the cerebellar

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primordium, in which the first differentiating cells appear by E15. By E17 the cerebellar primordium is transformed into the primitive cerebellum after a number of histogenetic changes. In the posterior pole of the cerebellar neuroepithelium, there is a specialized region known as the germinal trigone. From here, cells spread covering the entire surface of the cerebellar primordium and form a displaced secondary proliferative matrix known as the external germinal layer (EGL) where granule cell precursors proliferate. Beneath the spreading EGL, the Purkinje cell layer is formed. By E18–E20, the cerebellum acquires its typical lobular shape. When granule cells in the EGL exit the cell cycle they start to migrate along the fibers of Bergmann glial cells to the internal granular layer (IGL) where they complete their differentiation program. Migration of granule cells takes place postnatally in rodents and is completed by postnatal day (P) 20, when the EGL disappears. A striking and very characteristic feature of the hypothyroid cerebellum is a delay in the migration of granule cells so that the EGL persists beyond P20 (Nicholson and Altman, 1972).

63.2.3 Action of Thyroid Hormones on Myelination Hypothyroidism also causes delayed and poor deposition of myelin (Balazs et al., 1969; Malone et al., 1975; Noguchi and Sugisaki, 1984), whereas hyperthyroidism accelerates myelination (Adamo et al., 1990). The number of myelinated axons is lower in hypothyroid than in normal animals although most of the myelinated axons appear to have a normal thickness of the myelin sheath. Since maturation of axons is impaired in the hypothyroid animal (Berbel et al., 1994; Gravel et al., 1990) it is likely that the myelination deficit is partly due to a lower diameter of axons in hypothyroid animals, with normal myelination of those axons that reach a critical size (Notterpek and Rome, 1994).

63.2.4 Other Structural Defects Caused by Hypothyroidism The hypothyroid brain presents many structural defects (for an extensive review see Legrand (1984)) in addition to those outlined above. A reduction in the neuropil causes increments in cell density in the cerebral cortex (Eayrs and Taylor, 1951; Madeira et al., 1990). In regions with significant postnatal cell acquisitions, such as the olfactory bulb and the

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granular layers of the hippocampus and cerebellum, neonatal hypothyroidism is associated with lower cell numbers (Madeira et al., 1988a,b, 1991; Patel et al., 1976). This is probably due to decreased cell proliferation and increased cell death. In rodents, perinatal hypothyroidism causes decreased generation of mature GABAergic interneurons in the cerebellum and accumulation of GABAergic precursors (Manzano et al., 2007b). The number of interneurons is also reduced in the cerebral cortex of hypothyroid rats (Gilbert et al., 2007). Specific cell types display stunted dendritic and axonal growth and maturation (Gould and Butcher, 1989; Gravel et al., 1990). This is most evident in the Purkinje cells of the cerebellum which show markedly reduced dendritic arborization (Legrand, 1967). In the cerebral cortex the pyramidal cells of layer V have decreased number and altered distribution of dendritic spines along the apical dendrite (Ruiz-Marcos et al., 1980, 1982). Changes of dendritic spine number are also observed in the cortex and hippocampus after adult-onset hypothyroidism, and are reversible with thyroxine treatment (Gould et al., 1990; Ruiz-Marcos et al., 1988).

63.3 Thyroid Hormones in Brain 63.3.1 Sources of Thyroid Hormone for the Fetus Depending on the source of thyroid hormone available, three phases can be distinguished during development (Porterfield and Hendrich, 1993). Phase I extends from conception to the onset of fetal thyroid function (E17–E18 in the rat and second trimester in humans) and the only source of thyroid hormone is the maternal thyroid gland. Phase II extends from the onset of fetal thyroid function until birth and the tissues are exposed to both maternal and fetal hormones. Phase III starts with delivery, and only thyroid hormones from the neonate’s thyroid gland are available. During lactation the mother’s milk provides iodine, but the contribution of maternal hormone is negligible (Mallol et al., 1982). Thyroid hormones are present in the rat embryos as early as 3 days after implantation and in the fetus (Morreale de Escobar et al., 1985, 1987; Obrego´n et al., 1984; Porterfield and Hendrich, 1992; Woods et al., 1984) well before onset of fetal thyroid gland function (Nataf and Sfez, 1961). During fetal development the proportion of hormone available to the fetus originating in the fetal gland increases and that

of maternal origin decreases, but in the rat, before parturition, maternal T4 still accounts for about 17.5% of the fetal extrathyroidal thyroxine pool (Morreale de Escobar et al., 1990). In humans, Vulsma et al. (1989) found T4 concentrations of the order of 50–70 nM, that is, 50–70% of normal values, in the cord blood of neonates with congenital defects of the thyroid gland, so that the neonatal thyroid could not contribute to the thyroxine pool. Accordingly, after interruption of the maternal supply, the rate of disappearance of T4 from the neonate’s plasma agreed with its half-life. Therefore, the T4 present in these neonates could only have originated in the mothers’ thyroid gland, and the maternal contribution could be calculated (30–50%). Much earlier during development, T4 was found in the coelomic fluid bathing the yolk sac, as early as 6 gestational weeks (Contempre´ et al., 1993), and its concentration was positively correlated with maternal circulating T4. In the human fetal brain, T4 and T3 are present in significant amounts by the 10th week after conception (Bernal and Pekonen, 1984). The concentrations of T4 and T3 in the brain are controlled by very efficient regulatory mechanisms involving thyroidal secretion, transport to the brain, expression of deiodinases and, in the fetus, transplacental passage. In adult thyroidectomized rats treated with either T4 or T3 as a constant infusion, not all tissues normalized T3 concentrations simultaneously (Escobar-Morreale et al., 1995, 1999). When T3 alone was infused, the liver and kidney required lower doses than the brain for normalization of T3 concentration. This is because T3 equilibrates rapidly between the plasma, and liver or kidney pools. However, when T4 was administered, brain T3 was normalized at relatively low doses of T4 which resulted in low concentrations in plasma and other tissues. In addition, the brain T3 concentration was maintained within a narrow range under a wide range of T4 dosage. Similar observations were previously made regarding fetal brain T3 concentrations after hormonal treatment of hypothyroid dams (Calvo et al., 1990). In a situation of combined maternal and fetal hypothyroidism, the administration of T4 to the dams resulted in the appearance of T3 in the brain of the fetus at the end of gestation. When T3 was administered, it did not get to the brain, despite crossing the placenta and reaching other organs. These experiments clearly demonstrated that during fetal brain development, brain T3 derives largely

Thyroid Hormones and Brain Development

from T4, and that there is a restriction to blood T3. This is not the case in postnatal and adult rodents in which there is ample evidence that exogenous T3 has molecular and structural actions in the brain (Manzano et al., 2003). The content of T3 in the brain of postnatal mice with deletion of the type 2 deiodinase gene (see Section 63.3.2) was about 50% of normal, indicating that brain T3 derives partly from the blood and partly from local T4 deiodination (Galton et al., 2007). 63.3.2 Expression and Regional Distribution of Deiodinases Deiodinases have an important role in the regulation of local control of brain T3 concentrations. Deiodinases (D1, D2, and D3) are selenoproteins that catalyze the removal of iodine atoms from iodoaminoacids (Bianco and Larsen, 2005; St. Germain and Galton, 1997). D1 and D2 remove the iodine atom in the 50 position of the phenolic ring generating T3 from T4, thereby activating T4. D2 has the lowest Km (0.1 nM) of all deiodinases, and is inhibited by T4. This means that when the concentration of T4 decreases, the conversion of T4 to T3 is stimulated. D3 inactivates T4 and T3 after removal of the iodine in position 5 of the tyrosil ring, generating rT3 (reverse T3, 3,30 ,50 -triiodo-L-thyronine) from T4, and T2 (3,30 -diiodo-L-thyronine) from T3. Deiodinase activity is regulated by nutritional factors and the thyroidal state (Larsen and Berry, 1995). Thus, D2 increases in hypothyroidism whereas D1 and D3 decrease in hypothyroidism and increase in hyperthyroidism. The predominant deiodinases expressed in the brain are D2 and D3. Deiodinases are membrane-anchored proteins. It has been proposed that D1 and D3 are anchored to the plasma membrane with the catalytic site exposed to the intracellular (D1) or extracellular (D3) compartments, and that D2 is anchored to the endoplasmic reticulum, with the catalytic site exposed to the lumen (Bianco and Larsen, 2005). However, there is evidence that iodothyronines need to be internalized in the cell in order to act as D3 substrates (see Section 63.7.5). 63.3.2.1 Type 2 deiodinase

Most T3 present in D1-expressing tissues, such as the liver and kidney, is in rapid equilibrium with the plasma. In the brain, brown adipose tissue, and pituitary, which express D2, more than 50% of T3 derives from local T4 deiodination (Larsen et al., 1981;

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van Doorn et al., 1982). In the adult rat brain as much as 80% of nuclear-bound T3 is formed locally from T4 (Crantz et al., 1982). D2 activity is detectable in the brain of the rat fetus and increases markedly by the end of pregnancy to adult levels (Bates et al., 1999; Ruiz de On˜a et al., 1988). There is a concomitant 18fold increase of brain T3 during the same period (Ruiz de On˜a et al., 1988). D2 activity is very sensitive to the thyroidal status, and changes inversely to thyroid hormone concentrations. Thyroidectomy increases, and thyroid hormone administration decreases, D2 activity in the rat cerebral cortex (Leonard et al., 1981). Changes in D2 activity regulate T3 concentrations very tightly, and may protect the brain from either hypo- or hyperthyroidism. Under conditions of low iodine intake, an increased D2 activity helps to maintain normal T3 concentrations despite greatly reduced T4 concentrations in the plasma and brain (Obrego´n et al., 1991); this is one of the mechanisms maintaining euthyroidism in situations of moderate iodine deficiency leading to hypothyroxinemia (see Section 63.7.3). The main regulation of D2 activity occurs at the post-translational level involving the actin cytoskeleton (Farwell and Leonard, 1992; Farwell et al., 1993; Stachelek et al., 2000) and the ubiquitin-proteasome pathway (Steinsapir et al., 1998, 2000). In addition, D2 is also regulated at the mRNA level (Burmeister et al., 1997; Croteau et al., 1996; Guadan˜o-Ferraz et al., 1999; Tu et al., 1997). The highest levels of D2 expression in developing and adult rat brain were found in tanycytes, a specialized type of glial cell (Guadan˜o-Ferraz et al., 1997b; Tu et al., 1997). These cells line the walls of the lower-third, and the floor, of the third ventricle and extend long processes to the adjacent hypothalamus and the median eminence (Rodriguez et al., 1979). Within these locations, the tanycyte processes end in capillaries and axon terminals. Very high D2 activity is also found in this region (Riskind et al., 1987). Expression of D2 in the tanycytes suggests that these cells are involved in the uptake of T4 from the capillaries of the median eminence and basal hypothalamus and/or from the cereberospinal fluid (CS) and then convert it to T3. T3 formed in tanycytes could be released back to the CSF and reach other brain regions by diffusion, or it may be delivered to hypothalamic nuclei from the tanycyte processes. For example, in this manner T3 could reach the paraventricular nucleus (PVN) where T3 regulates thyrotropin-releasing hormone (TRH) production. This could explain why D2 is absent from the PVN,

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despite the importance of T3 generated from T4 in TRH regulation (Fliers et al., 2006a; Guadan˜oFerraz et al., 1997b; Riskind et al., 1987). T3 produced by tanycytes could also participate in anterior pituitary regulation after delivery to the portal vessels (Lechan and Fekete, 2007). In addition to tanycytes, D2 is expressed in astrocytes throughout the brain (Fliers et al., 2006b; Guadan˜o-Ferraz et al., 1997b, 1999). In hypothyroid rats, D2 expression increases especially in areas of primary sensory systems, most notably in somatosensory pathways, such as the auditory pathway, pointing to a selective protection of these areas against T3 deficiency (Guadan˜o-Ferraz et al., 1999). In relation to D2 expression in the central pathways of hearing, D2 is expressed at very high levels in the cochlea (Campos-Barros et al., 2000), just before the onset of hearing, and D2 knockout (KO) mice have retarded cochlear develeopent and loss of auditory function (Ng et al., 2004). The location of D2 mRNA in glial cells agrees with earlier studies demonstrating that D2 activity is present in astrocyte cultures (Cavalieri et al., 1986; Courtin et al., 1986; Leonard et al., 1990). Although, in hypothyroid rats, D2 may also be expressed in some interneurons (Guadan˜o-Ferraz et al., 1999), the predominant expression of D2 in astrocytes contrasts with the localization of the T3 receptor, which is mainly neuronal (Bradley et al., 1992; Mellstro¨m et al., 1991). Therefore, it is feasible that astrocytes are involved in the uptake of T4 from the capillaries and in T3 generation and delivery to neurons. This is reminiscent of other forms of coupling between glia and neurons (Tsacopoulos and Magistretti, 1996). A similar situation takes place in the cochlea, where D2 is present in the connective tissue (CamposBarros et al., 2000) whereas the T3 receptor is expressed in the sensory epithelium and spiral ganglion (Bradley et al., 1994; Campos-Barros et al., 2000; Lauterman and ten Cate, 1997). In agreement with the anatomical and physiological evidence supporting an important role of D2 in the generation of brain T3, D2 KO mice (Galton et al., 2007) have reduced T3 concentrations, in the brain, which were similar to those of hypothyroid mice; however, they had minimal neurological impairment. Tests of locomotion, memory, anxiety, etc., were normal or gave minimal impairment. The expression of T3-responsive genes was altered in the hypothyroid mice but not in the D2 null mice despite having similar T3 concentrations in the brain. The cause for this discrepancy is not known, but one

intriguing possibility is that T3 generated locally from T4 has a different role than T3 reaching the neurons directly from the blood. 63.3.2.2 Type 3 deiodinase

Another important control of T3 concentrations is carried out by D3, the enzyme that inactivates thyroid hormones through inner-ring deiodination (St. Germain, 1995). D3 activity is highest in the placenta and fetal tissues and its activity decreases after birth, in contrast to D1and D2 (Bates et al., 1999; Kaplan and Yaskoski, 1981; Santini et al., 1999; Schro¨der-van der Elst et al., 1998). In the human placenta, D3 activity is 200 times higher than that of D2 at all gestational ages (Kaplan and Shaw, 1984; Koopdonk-Kool et al., 1996). In the adult rat, D3 expression is limited to the skin, brain, and uterus. D3 has been cloned from amphibia (St. Germain et al., 1994) and mammals (Croteau et al., 1995; Herna´ndez et al., 1999; Salvatore et al., 1995). D3 is expressed in cultured astrocytes and is induced by growth factors, T3, and retinoic acid (Courtin et al., 1991; Esfandiari et al., 1992, 1994). However, in vivo, the D3 mRNA is clearly located in neurons (Esca´mez et al., 1999; Tu et al., 1999). D3 plays an important role in the control of T3 concentration in developing tissues. Its role in metamorphosis, as a modulator of the sensitivity to thyroid hormone has been clearly established. There is a negative correlation between expression of D3 and responsiveness to thyroid hormone of different tadpole tissues (Becker et al., 1997; Berry et al., 1998; Marsh-Armstrong et al., 1999), and overexpression of D3 in transgenic tadpoles strongly inhibits metamorphosis (Huang et al., 1998). In mammals, high expression of D3 in the placenta controls the transfer of maternal thyroid hormone to the fetus (Mortimer et al., 1996), and D3 expression is very high in the uterus at the implantation site and in the epithelial cells of the uterine lumen surrounding the fetal cavity (Galton et al., 1999). In the newborn rat brain, discrete and intense expression of D3 occur in neurons located in areas involved in sexual differentiation of the brain (Baum, 1999; Esca´mez et al., 1999), suggesting that these areas need to be protected from a possible interfering action of T3 during critical periods of sexual brain differentiation (Dellovade et al., 1996). Null mutant mice for D3 have been generated (Hernandez et al., 2006, 2007). These mice have profound alterations in thyroid hormone economy, with greatly elevated thyroid hormone concentrations during the perinatal period, which then progresses into a

Thyroid Hormones and Brain Development

state of central hypothyroidism, which is maintained through adulthood. In the brain, the expression of thyroid hormone target genes is elevated during the early postnatal period, and then decreases, in parallel to the thyroid state.

63.3.3 Transport of Thyroid Hormones to the Brain 63.3.3.1 The brain barriers

The passage of substances from the blood to the brain is restricted by the blood–brain and the blood– cerebrospinal fluid (blood–CSF) barriers (Laterra and Goldstein, 2000). The blood–brain barrier (BBB) is formed by the endothelial cells of brain capillaries which are tightly apposed by tight junctions. Surrounding the brain capillaries are the astrocytic end feet. The blood–CSF barrier is formed by the epithelial cells lining the ventricular side of the choroid plexus. Administration of labeled T4 or T3 leads to a rapid labeling of the choroid plexus and the appearance of the hormones in the CSF (Hagen and Solberg, 1974). Thyroid hormones are present in the CSF at less than 10 times the concentration in serum (Hagen and Elliot, 1973; Kirkegaard and Faber, 1991; Thompson et al., 1982), but the free hormone fraction is several-fold higher in the CSF due to the low protein concentration. It was suggested that transthyretin (TTR), the major protein of the CSF in many species, plays a role in T4 transport in the choroid plexus (Dickson et al., 1987; Schreiber et al., 1995). However, the T4 transfer rate from plasma to tissue compartments, including the brain, is normal in TTR nullmutant mice (Palha et al., 1994, 1997). The passage of thyroid hormones from the CSF to the brain parenchyma is limited, since labeled T4 injected directly into the CSF accumulates in the median eminence, with only a small fraction of the label present in other structures (Dratman et al., 1991; Kendall et al., 1971). The fraction of brain thyroid hormone that is transported through the choroid plexus and the CSF has been estimated to be around 20% (Chanoine et al., 1992). The bulk of the hormone that reaches most brain structures does so through the capillaries in the parenchyma. 63.3.3.2 Thyroid hormone transporters

Until recently, it was assumed that the uptake of thyroid hormones by target cells was by diffusion through the plasma membrane. Several membrane transporters for thyroid hormones were described,

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but definitive demonstration for their role in thyroid hormone metabolism and action came from the finding that mutations in one of these transporters, the monocarboxylate transporter 8 (MCT8), caused a syndrome of severe neurological impairment and thyroid hormone abnormalities (Dumitrescu et al., 2004; Friesema et al., 2004; see Section 63.7). The membrane transporters for thyroid hormones belong to several families including the Naþ-dependent organic anion transporter (NTCP), the Naþ-independent organic anion transporting polypeptides (OATP), the heterodimeric amino acid transporters (HAT), and the monocarboxylate anion transporters (MCT). These transporters have a wide range of tissue distribution, with overlapping patterns of expression in most of them (Friesema et al., 2005). Of relevance to the action of thyroid hormone in the brain is that MCT8 is expressed in the epithelial cells of the choroid plexus, in the tanycytes, and in neurons, whereas OATP is expressed in the endothelial cells of the capillaries forming the BBB, and in the choroid plexus (Heuer et al., 2005). Also, OATP has higher affinity for T4 than for T3, whereas MCT8 has higher affinity for T3 than for T4. Therefore, and taking into account the expression of D2 in the astrocytes, which are in contact with the BBB, it seems that T4 enters the brain through the OATP transporter in the BBB, is converted to T3 in the astrocytes, and the T3 formed is transported to the neurons via MCT8.

63.4 Thyroid Hormone Action 63.4.1 The Nuclear Pathway of Thyroid Hormone Action Most actions of thyroid hormones are exerted at the nuclear level after interaction of T3 with specific high-affinity nuclear receptors, which are ligandmodulated transcription factors (Flamant et al., 2006; Oetting and Yen, 2007; Yen, 2001). In mammals there are three main receptor types which are products of two genes known as thyroid hormone receptor a (TRa) and TRb, located in different chromosomes (17 and 3 respectively, in humans). TR genes encode several protein products: TRa1 and TRa2, and TRb1 and TRb2, respectively. In the rat, additional TRb isoforms, TRb3 and the truncated protein DTRb3 are also present (Harvey et al., 2007). The TRa isoforms differ in the C-terminus, and are generated by alternative splicing. The TRb isoforms differ at the N-terminus and are generated by alternative splicing and differential

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promoter usage. TRa2 (Izumo and Mahdavi, 1988) does not bind hormone but has an intact DNA-binding domain. It is not present in the chicken or in amphibians. Its physiological role is unknown and it may function as an antagonist of the functional receptors because, in transfected cells, it inhibits the transcriptional activation by TRs (Koenig et al., 1989; Lazar et al., 1989a). However, neurons expressing TRa2 are sensitive to T3 in vivo (Guadan˜o-Ferraz et al., 1997a). TRa2 deletion in mice has not given clear insights as to its physiological role (Salto et al., 2001). The TRa gene also encodes an orphan receptor known as rev-ErbAa. The rev-ErbAa gene partially overlaps the TRa gene and is transcribed from the opposite strand (Lazar et al., 1989b; Miyajima et al., 1989). Little is known of its physiological role, but mutant mice show cerebellar developmental defects (Chomez et al., 2000). The products of the TRb gene, TRb1 and TRb2, are identical except for the amino terminus. 63.4.2 Modulation of Transcription by Nuclear Receptors for Thyroid Hormone The T3 receptors modulate transcription mainly by binding to specific DNA sequences known as T3 response elements (TRE). These consist of repeats of the basic hexameric sequence AGGT/ACA in several different arrangements, such as direct repeats separated by a spacer of 4 bp (DR4: rat malic enzyme, rat cardiac heavy myosin alpha chain, brain RC3), everted repeats separated by 6 bp (ER6: chicken lysozyme, rat myelin basic protein), and other configurations (Ribeiro et al., 1998). In the most prevalent model of T3 action, the TRs act as heterodimers with retinoid X receptor (RXR), the 9-cis retinoic acid receptor. The TR-RXR heterodimer binds to the TRE with a polarity such that the TR sits on the 30 half-site. In addition to the RXR partner, many other molecules have been shown to be directly or indirectly associated to the TR functionally. These associations often represent links with other signaling pathways that allow the integration of diverse physiological signals. Since RXR is a receptor itself, and also a partner for other nuclear receptors, its engagement in other activation pathways may modify the cellular response to T3. For instance, mutual interference between vitamin D3 and T3 signaling has been described (Garcı´a-Villalba et al., 1996). TRs form heterodimers with other members of the receptor superfamily, such as vitamin D3 receptor or the peroxisome proliferator-activated receptor (PPAR), and their activity can be modulated by COUP-TF and

other orphan receptors (Cooney et al., 1993). Some actions of the nuclear receptors are also mediated through direct interactions with other nuclear proteins, without binding to genomic regulatory sites. One example is the interference with the AP-1 pathway (Caelles et al., 1997; Kamei et al., 1996). The receptors have T3-dependent and T3independent actions. In the absence of T3, they usually not only act as transcriptional repressors (Sap et al., 1989), but they can also activate gene expression, especially the TRb2 isoform (Langlois et al., 1997; Oberste-Berghaus et al., 2000; Yang et al., 1999). In the simplest model of TR action, the ligand-free TR, or aporeceptor, represses gene transcription by recruiting other regulatory proteins called corepressors. The corepressors nuclear receptor corepressor (N-CoR), or silencing mediator for retinoic and thyroid receptor (SMRT), bind to the TR and form the core of a large corepressor complex containing proteins with histone deacetylase activity, such as HDAC3 (Ishizuka and Lazar, 2003). Deacetylated histones keep the chromatin in a compact conformation with repression of transcription. Hormone-binding induces a conformational change of the receptor with release of corepressors and recruitment of coactivators (Nagy and Schwabe, 2004), p160/SCR-1 (steroid receptor coactivator) and the histone acetyl transferases CBP/p300 and pCAF. Histone acetylation modifies chromatin structure and facilitates the recruitment of the basal transcription machinery. In the current model of nuclear receptor action, the coactivators and corepressors are part of large multisubunit complexes that contain other enzymatic activities, in addition to acetyl transferases and deacetylases, such as methylases, kinases, phosphatases, ATP-dependent chromatin remodeling enzymes, and others (Rosenfeld et al., 2006). The individual components of these complexes interact in a combinatorial way with the nuclear receptors, and their activity can also be modified by covalent modifications from cellular signaling cascades. All this provides a high degree of flexibility and specificity for the tight control of developmental and physiological process. 63.4.3 Extragenomic Pathways of Thyroid Hormone Action Extragenomic pathways of thyroid hormone action have also been described (Oetting and Yen, 2007), but their contribution to the physiological actions of thyroid hormones in vivo are still unknown. In one model, T4 and T3 bind to a membrane receptor formed by the integrin aVb3, which then transduces

Thyroid Hormones and Brain Development

the hormonal signal to the mitogen-activated protein kinase (MAPK) signaling cascade (Davis et al., 2005). This results in phosphorylation of nuclear targets such as the TR and other transcription factors. In this way, thyroid hormones, acting at the cell membrane, can influence the activity of nuclear proteins including TRs. The TR also shuttles between the nucleus and the cytoplasm; in the cytoplasm, the TR can interact with p85, the regulatory subunit of phosphatidyl inositol 3-kinase regulating downstream targets such as mammalian target of rapamycin (mTOR; Cao et al., 2005) or Rac (Storey et al., 2006). An emerging new field is that of the activity and physiological role of iodothyronine metabolites generated after decarboxylation. These metabolites are known as thyronamines (TAM): T1AM, derived from 3-iodothyroxine, T3AM, or triam, derived from T3, or T4AM,or thyroxamine, derived from T4 (Braulke et al., 2008; Doyle et al., 2007; Pietsch et al., 2007; Scanlan et al., 2004). These derivatives perform fast actions, such as hypothermia and bradycardia, acting through the G-protein-coupled receptors called trace amine-associated receptors (TAAR).

63.5 Nuclear Thyroid Hormone Receptors in the Brain In rats, the receptor protein can be detected in isolated cell nuclei from whole brain at E13.5–14, that is, several days before onset of thyroid gland function. The receptor increased subsequently and reached a maximum on P6 (Pe´rez-Castillo et al., 1985; Schwartz and Oppenheimer, 1978; Strait et al., 1990). Total brain receptor occupancy by the 500 Receptor

hormone increases in parallel with plasma and cytosol total and free T3 with a maximum of 50–60% on P15 (Ferreiro et al., 1990). All receptor isoform mRNAs are expressed in the brain, but the predominant TR isoform is TRa1 which is widely distributed in the CNS from E14 to adulthood (Bradley et al., 1989, 1992; Mellstro¨m et al., 1991). From E19 to P0, TRa1 is present in the outer part of the cerebral cortex and hippocampal CA1 field. During the late fetal stage, TRa1 becomes expressed in the piriform cortex, superior colliculus, all pyramidal fields of the hippocampus, and in the granular layer of dentate gyrus. In adult rats, TRa1 expression is prominent in the cerebral cortex, cerebellum, hippocampus, striatum, and olfactory bulb. The pattern of TRb1 expression during development is different from that of TRa1, with restricted low expression during the fetal period, and increasing expression during the postnatal period and through adulthood. TRb1 mRNA can be detected at E15.5 in the upper tegmental neuroepithelium. Between E17 and E20 only low levels are present in the brain, especially in the CA1 field of the hippocampus. On P0 a drastic increase occurs in the accumbens, striatum, and hippocampal CA1 field. From around P7 TRb1 also becomes expressed in the cerebral cortex. In the human brain, the receptor protein is present at low levels in the fetal brain around the 10th week postconception (Bernal and Pekonen, 1984). The T3-receptor mRNAs can be detected during the first trimester (Iskaros et al., 2000). Receptor concentration increases tenfold from the 10th to the 16th–18th weeks postconception (Figure 1). During this time, the brain gains in weight and DNA content by about fivefold, so that the total brain T3 receptor Cerebellum (high D3)

Cortex (high D2)

400 300

2

200

1

T3

2013

2 T3 1

100 0

0 8 10 12 14 16 18 20

0 12 14 16 18 20 12 14 16 18 20 Weeks of gestation

Weeks

(a)

(b)

Start fetal thyroid function

Figure 1 T3 receptor and T3 content of the human fetal brain during the second trimester. (a) T3 receptor. (b) T3 concentrations in the cortex, a region with D2 and low D3 activity, and the cerebellum, a region with low D2 and high D3 activity. (a) Adapted from Bernal J and Pekonen F (1984) Ontogenesis of the nuclear 3,5,30 -triiodothyronine receptor in the human fetal brain. Endocrinology 114: 677–679. (b) Adapted from Kester MH, Martinez de Mena R, Obregon MJ, et al. (2004) Iodothyronine levels in the human developing brain: Major regulatory roles of iodothyronine deiodinases in different areas. Journal of Clinical Endocrinology and Metabolism 89: 3117–3128.

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Thyroid Hormones and Brain Development

content increases 500 times. This period coincides with that of the active neuroblast proliferation (Dobbing and Sands, 1970). T3 was also present in brain from the 10th week of gestation, at concentrations enough to account for about 25% occupancy of receptor (Ferreiro et al., 1988). In contrast, other organs, such as the liver and lungs, with high receptor concentration, only T4 was present at 18th week. This suggests that T3 derives locally from T4 due to early local expression of D2. Local regulation of T3 concentration in the brain during the second trimester has been confirmed by Kester et al. (2004). These authors showed an increased T3 content in the cerebral cortex during the second trimester, in parallel with an increased D2 activity. In contrast, in the cerebellum high activity of D3 kept T3 concentrations low (Figure 1). These data are especially relevant in the context of the pathogenesis of neurological cretinism and for the consequences of maternal hypothyroxinemia on fetal brain development, as discussed in Section 63.7.3. The patterns of mRNA distribution and concentrations may not reflect those of the encoded proteins. This is due to differences in translational efficiency of the corresponding mRNAs, and in the relative half-lives of the mRNAs and the encoded proteins. The TRb2 isoform, initially considered to be pituitary specific (Hodin et al., 1989), was later detected by in situ hybridization in several regions of the brain such as the rostral caudate, the hippocampus, and the hypothalamus (Bradley et al., 1992). Actually the TRb2 protein contributes by about 10% to the total receptor protein in different tissues, including the brain (Schwartz et al., 1994). By immunohistochemistry, the TRb2 protein has been found widely distributed in the brain, in regions where the mRNA cannot be detected, such as layers II–VI of the cerebral cortex, and Purkinje cells of the cerebellum (Lechan et al., 1993). Quantitative studies on the concentrations of TR mRNAs and proteins in different tissues were carried out by Ercan-Fang et al. (1996; Table 1). The distribution of T3 receptor mRNAs in vivo by in situ hybridization suggests a predominant neuronal expression. However, in brain cell cultures, T3 receptors have been detected in neurons, astrocytes, and oligodendrocytes (Luo et al., 1986; Yusta et al., 1988). In dorsal root ganglia, both sensory neurons and Schwann cells appear to express T3 receptors (Glauser and Barakat-Walter, 1997) but whereas neurons express the receptor permanently, glial cells do so only transiently (Barakat-Walter and Droz, 1995).

Table 1 TR isoform protein and mRNA concentrations in rat tissues Protein molecules/cell

mRNA molecules/cell

TRa1 Pituitary Liver Brain Kidney Heart

2310 963 2360 626 1300

0.128 1.11 16.4 2.50 2.70

TRb1 Pituitary Liver Brain Kidney Heart

1470 3900 819 578 1460

0.873 5.10 20.2 13.5 7.37

TRb2 Pituitary Liver Brain Kidney Heart

5240 829 328 178 506

0.631 <0.00689 <0.00684 <0.00501 <0.00453

The three TR isoform proteins are present in all tissues. This includes the TRb2 isoform, despite that the corresponding mRNA is only detectable in pituitary. The concentrations of receptor protein were measured by specific immunoprecipitation of labeled T3 after incubation with tissue nuclear extract. The concentrations of mRNA were measured in Northern blots using quantitative procedures. Data from Ercan-Fang S, Schwartz HL, and Oppenheimer JH (1996) Isoform specific 3,5,30 -triiodothyronine receptor binding capacity and messenger ribonucleic acid content in rat adenohypophysis: Effect of thyroidal state and comparison with extrapituitary tissues. Endocrinology 137: 3228–3233.

Studies in vivo have shown that TR isoforms colocalize with oligodendrocyte markers but not with astrocytic markers (Carlson et al., 1994) and other studies have demonstrated that, in primary culture, rat astrocytes do not express T3 receptor, but only the TRa2 isoform (Kolodny et al., 1985; Leonard et al., 1994). We find that cerebellar astrocytes express both, TRa1 and TRb1 (Manzano et al., 2007a).

63.6 Mechanisms of Thyroid Hormone Action in the Brain 63.6.1 Regulation of Brain Gene Expression by Thyroid Hormone The effects of thyroid hormones acting via nuclear receptors on developmental processes are carried out through the control of gene expression. Most of the thyroid hormone-dependent genes identified so far are expressed and regulated by thyroid hormone during the postnatal period and the role of thyroid hormone is to accelerate developmental changes of

Thyroid Hormones and Brain Development

gene expression. Another property of thyroid hormone regulation of gene expression in the brain is the regional specificity, even for genes regulated at the transcriptional level (Figure 2). The molecular basis for this is not known. Most of the thyroid hormone-regulated genes in the rat brain are sensitive to the hormone only during a narrow window during the postnatal period (Figures 2 and 3). This suggests that the critical period of thyroid hormone sensitivity in the brain is limited to the first 2–3 postnatal weeks in the rat. In humans, the sensitive period would correspondingly start after midpregnancy. However, there may be a bias in this concept, derived from the fact that most searches for thyroid hormone-dependent genes in

P0 l P0 CP CP P5 l P5 ll-lll

ll-lll H

RC3/neurogranin mRNA

N

brain have been made during the postnatal period, at the peak of T3 receptor expression and occupancy. As already indicated, maternal hormones have recently been demonstrated to play an important role in cell migration in the fetal neocortex (Auso´ et al., 2004), much before the onset of fetal thyroid gland function. Genes regulated in the fetal brain by maternal hormones are yet to be identified, and application of global analysis of gene expression using suitable models of fetal hypothyroidism may help to identify thyroid hormone-regulated genes during fetal brain development. Microarray techniques have been used recently to search for thyroid hormone-regulated genes in the postnatal cerebellum (Dong et al., 2005; Martel et al., 2002; Miller et al., 2004; Poguet et al., 2003; Quignodon et al., 2007a). 63.6.2 Mechanisms of Action of Thyroid Hormones on Myelination

Reelin protein

N

2015

H

Figure 2 Examples of the time and region-specific regulation of gene expression by thyroid hormone. The upper panel shows an immunohistochemistry for Reelin in the cerebral cortex of normal and hypothyroid rats at P0 and P5. An effect of hypothyroidism on Reelin expression can be seen at P0 but not at P5. The lower panel shows in situ hybridization for RC3 in normal and hypothyroid rats at P15. Hypothyroidism induces an almost complete absence of expression in the caudate, but it is much less effective in the cerebral cortex. Adapted from Alvarez-Dolado M, Ruiz M, del Rio JA, et al. (1999b) Thyroid hormone regulates reelin and dab1 expression during brain development. Journal of Neuroscience 19: 6979–6993; In˜iguez MA, de Lecea L, Guadan˜o-Ferraz A, Morte B, Gerendasy D, Sutcliffe JG, and Bernal J (1996) Cell-specific effects of thyroid hormone on RC3/neurogranin expression in rat brain. Endocrinology 137: 1032–1041.

In vivo, thyroid hormone influences the expression of many myelin genes. The best characterized are those encoding the structural proteins (proteolipid protein (PLP), myelin basic protein (MBP), and myelin associated glycoprotein (MAG; Sutcliffe, 1988)). The period of thyroid hormone sensitivity for these genes in the rat brain extends from about the end of the first postnatal week up to the end of the first month, but the timing of regulation has a strong regional component. Not all regions myelinate simultaneously, and sensitivity to thyroid hormones follow the myelination wave, from caudal to rostral areas. In caudal regions, such as the cerebellum, myelin mRNA and proteins are reduced in hypothyroid rats, compared to normal rats, only around P10, whereas in rostral regions such as the cortex and hippocampus, the differences persist until about P20–P25 (Ibarrola and Rodriguez-Pen˜a, 1997; Rodriguez-Pena et al., 1993). In all cases, expression of myelin genes becomes normalized with age, even in the absence of thyroid hormone treatment. The role of thyroid hormones is to accelerate the myelination process, and myelin genes become refractory to thyroid hormones in adult individuals. The primary action of thyroid hormone probably is on oligodendrocyte differentiation, since thyroid hormone in vivo promotes accumulation of differentiated oligodendrocytes, and therefore the expression of oligodendrocyte-specific genes (Schoonover et al., 2004). Thyroid hormone promotes differentiation of oligodendrocyte precursors in vitro (Gao et al., 1998). The effect is probably exerted through inhibition of

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Thyroid Hormones and Brain Development

EC matrix, adhesion molecules L1 Reelin (cerebellum) Reelin (cortex) Tenascin Laminin NCAM

Upregulated by T3 Downregulated by T3

RNA splicing Musashi Signaling Rhes/RasD2

Cox-1

RC3/Neurogranin Purkinje PCP2 CamKIV RORα MBP, PLP, MAG, CNP

Myelin

β5-Tubulin α1, β2-Tubulin

Tubulin Neurotrophins p75NTR

trkA NGF P0

P10

P20

Adult

Figure 3 Simplified scheme showing the approximate individual windows of T3 regulation of brain genes.

the transcription factor E2F1 (Nygard et al., 2003). Although earlier claims attributed a prominent role to TRb in the thyroid hormone control of oligodendrocyte differentiation, more recent studies employing TRa1-deficient animals have demonstrated that the relevant receptor is TRa1 (Billon et al., 2001, 2002).

mRNAs, such as 12S and 16S RNAs and cytochrome c oxidase subunits (Vega-Nu´n˜ez et al., 1995), a protein import receptor (Alvarez-Dolado et al., 1999a), NADH dehydrogenase subunit 3 (Iglesias et al., 1995), and other RNAs. An extensive review of thyroid hormone action on the mitochondria has been published (Wrutniak-Cabello et al., 2001).

63.6.3 Mitochondrial Actions of Thyroid Hormones

63.6.4

Thyroid treatment in vivo increases the transcriptional activity of mitochondrial preparations (Barsano et al., 1977) and addition of T3 in vitro to isolated mitochondria selectively increases the proportion of mRNA over total mitochondrial RNA (Enriquez et al., 1999). The mitochondria contain truncated forms of TRa1 and RXRa (Casas et al., 2003). In the brain, changes of the thyroid status influence mitochondrial morphology and function (Vega-Nu´n˜ez et al., 1997) and lead to changes in the expression of nuclear-encoded and mitochondrial-encoded

Control of Cell Migration

The mechanisms by which thyroid hormone influences migration have not been defined with certainty although some molecules involved in migration have been found to be under thyroid hormone regulation. It is also important that maturation of the radial glia, the path along which radial migration in the neocortex and hippocampus takes place, is altered by maternal hypothyroidism (Martinez-Galan et al., 1997). Among relevant molecules involved in migration, the protein Reelin is under thyroid hormone control in the cortex and cerebellum (Alvarez-Dolado et al., 1999b). Reelin is an extracellular molecule, secreted by

Thyroid Hormones and Brain Development

Cajal-Retzius cells (Del Rio et al., 1997) of cerebral cortex layer I and hippocampus and by granule cells of the cerebellum that play an important role in migration. Its main function is to signal the migrating neurons regarding when to stop. Its activity is essential for the inside-out pattern of cerebral cortex development, by which the newly generated neurons in the ventricular layer migrate through the surface of the cortex, passing the earlier-generated cells displacing them to the inner side of the cortex. The protein Disabled1 (Dab1), a component of the Reelin signaling pathway is also under thyroid hormone regulation (Del Rio et al., 1997). Other extracellular matrix proteins and adhesion molecules might mediate some of the effects of thyroid hormone on neuron migration. These include Tenascin C, laminin, L1, NCAM (Alvarez-Dolado et al., 1998, 2000; Farwell and Dubord-Tomasetti, 1999; Iglesias et al., 1996). These proteins are downregulated by thyroid hormones, so that in hypothyroid animals their concentration is increased. In general, these proteins present high concentrations in the fetal neural tissue and then decrease progressively after birth during the postnatal period. In the absence of thyroid hormone, this decreased concentration is delayed and proceeds at a slower rate than in its presence. The consequences of regulation by thyroid hormone might not be limited to cell migration, since these molecules have been implicated in many different processes in the developing brain, such as neurite outgrowth, growth cone morphology, and axonal guidance and fasciculation. 63.6.5

Control of Neural Cell Differentiation

Thyroid hormone controls the expression of many proteins that have roles on terminal cell differentiation, including cell cycle regulators, cytoskeletal proteins, neurotrophins and neurotrophin receptors, and extracellular matrix proteins. Among the cell cycle regulators, thyroid hormone regulates the expression of E2F1, p53, cyclins, and cyclin-dependent kinase inhibitors (Pe´rez-Juste and Aranda, 1999; Qi et al., 1999; Wood et al., 2002) but the regional and temporal patterns of in vivo regulation, as well as the cellular types in which such regulation is relevant, are unknown, with the possible exception of the implication of E2F1 in oligodendrocyte differentiation, as already mentioned (Nygard et al., 2003). The shape of neural cells is determined by the cytoskeleton, which consists of microtubules (Tubulin), microfilaments (Actin), and intermediate filaments

2017

which may be specific for neurons (Neurofilaments), glia (glial fibrillary acidic protein), or maturing cells (Vimentin, Nestin). The influence of thyroid hormone on the expression of cytoskeletal components is an important mediator of the effects of the hormone on morphological differentiation and axonal and dendritic outgrowth. Thyroid hormone regulates the expression of the gene encoding tubulins a1, a2, which are downregulated, and b4 which is upregulated (Aniello et al., 1991b; Lorenzo et al., 2002). Some microtubule associated proteins (MAPs) are also under thyroid hormone control but at a post-transcriptional level. For example, MAP2 is regulated at the level of protein distribution in the Purkinje cell dendritic tree (Silva and Rudas, 1990). The conversion of immature to mature forms of the TAU protein, a process that occurs during development by alternative splicing of the TAU mRNA, is under thyroid hormone regulation (Aniello et al., 1991a). Differentiation of glial cells other than oligodendrocytes is also influenced by thyroid hormones, including astrocytes (Lima et al., 1998; Manzano et al., 2007a), cerebellar Golgi epithelial cells (Clos et al., 1980), and microglia (Lima et al., 2001). As mentioned above, thyroid hormone influences the in vivo expression of astroglial genes, such as those encoding Tenascin C, Laminin, and L1, which also have additional roles in neuronal migration and differentiation, and in axonal fasciculation. In vitro, the effect of T3 on astrocyte differentiation is blocked by b-adrenergic receptor antagonists (Gharami and Das, 2000). Some of the effects of thyroid hormone on differentiation and survival might also be mediated through control of neurotrophin expression. Interactions between thyroid hormone and nerve growth factor (NGF) are known to be relevant for the growth and maintenance of cholinergic neurons in the basal forebrain (Gould and Butcher, 1989) and other structures, and more recently, changes in NGF, trkA, and p75NTR after hypothyroidism have been described (Alvarez-Dolado et al., 1994). In the cerebellum, thyroid hormone also controls the expression of NT-3 in vivo and in cultured cerebellar granule cells, and it was suggested that the control of Purkinje cell differentiation by thyroid hormone is mediated through NT-3 produced by granule cells (Lindholm et al., 1993). 63.6.6 Regulation of the Expression of Genes Involved in Signaling In addition to the proteins already mentioned, other proteins directly involved in intracellular signaling

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Thyroid Hormones and Brain Development

are also under direct control of thyroid hormone. One of these proteins is RC3 (also known as neurogranin), a protein kinase C substrate that binds calmodulin in the nonphosphorylated state and in the presence of low Ca2+ concentrations (Gerendasy and Sutcliffe, 1997). RC3 is thought to play a role in the cascade of events triggered by the binding of glutamate to NMDA receptors in the postsynaptic neurons. Entry of calcium into the cell and activation of PKC induces RC3 phosphorylation and release of RC3-bound calmodulin. Free calmodulin is then avalaible for activation of calmodulin targets, including calmodulin kinase II, nitric oxide synthase, and other important targets. RC3 KO mice display alterations of spatial memory (Miyakawa et al., 2001). RC3 mRNA and protein are under thyroid hormone control in developing rats, mice, and goats. Thyroid hormone exerts a restricted regional control of RC3 expression (In˜iguez et al., 1996) limited to the retrosplenial and layer 6 of cerebral cortex, the caudate, and the dentate gyrus. In adult animals, RC3 continues to be sensitive to thyroid hormones in the caudate. The mechanism of RC3 induction by T3 is exerted at the transcriptional level and the RC3 gene contains a thyroid hormone-responsive element of the direct repeat type in the first intron (Martinez de Arrieta et al., 1999). RC3 is a good marker of thyroid hormone action in the brain of rats and mice. Rhes (Vargiu et al., 2001, 2004) is a protein of the Ras family, greatly enriched in the striatum (hence its name, Ras homolog enriched in striatum), with high homology with Dexras-1, a dexamethasone-inducible Ras protein. These two proteins define a new family within the Ras superfamily of small GTPases. Little is still known on the function of these proteins, but they appear to be involved in G-protein signaling. PCP-2 is a protein specific of Purkinje cells. It contains the G-protein regulatory motif GoLoco, involved in regulation of Gai protein signaling (Luo and Denker, 1999). As with other targets of thyroid hormone, it is dependent of thyroid hormone in vivo during a short window during the postnatal period, reaching normal expression in adult animals even in the face of continuing hypothyroidism, and in the absence of thyroid hormone treatment. Thyroid hormone also regulates, in vivo and in cultured cells, the expression of tubby, a gene expressed in hypothalamic nuclei encoding a protein that also acts through G-protein signaling (Koritschoner et al., 2001; Santagata et al., 2001). Deletion of the tubby gene in mice causes insulin resistance, obesity, and sensory deficits.

63.6.7 Transcription Factors and Splicing Regulators Regulation of proteins involved in transcription, stability of mRNA, and splicing is potentially very important since these proteins occupy a top position in the hierarchy of gene regulation. Among the transcription factors, NGFI-A mRNA (Krox-24, Egr-1, Zif-268) is decreased in hypothyroid rats in several areas of the brain (Mellstro¨m et al., 1994), and is induced by T3 at the promoter level in vivo (Ghorbel et al., 1999). T3 regulates the transcription factor basic transcription element binding protein (BTEB), a member of the Sp1 family of transcription factors, in vivo and in cultured neuronal cells, where it is regulated specifically by TRb1, and not by TRa1. BTEB induction is important in the T3 stimulation of neurite outgrowth (Cayrou et al., 2002; Denver et al., 1999). RORa, a member of the RZR/ROR family of orphan nuclear receptors is thyroid hormone dependent in the cerebellum. Disruption of the RORa gene leads to profound alterations in Purkinje cell growth and differentiation and granule cell migration (staggerer phenotype in mice) so that some of the actions of thyroid hormone on the cerebellum could be mediated by this transcription factor (Koibuchi and Chin, 1998). Also in the cerebellum, the expression of the transcription factor Hairless is strongly dependent on the thyroid status (Thompson, 1996). The Hairless protein is a corepressor that forms heterodimers with the TR (Thompson and Bottcher, 1997). Finally, thyroid hormone regulates the expression of genes involved in RNA splicing, such as the mammalian homolog of the Drosophila splicing regulator Suppressor-of-white-apricot (SWAP; Cuadrado et al., 1999), and musashi-1. Some of the post-transcriptional effects of thyroid hormone might be mediated through the control of RNAbinding proteins controlling RNA stability.

63.6.8 Mechanisms of Gene Regulation by Thyroid Hormone In some cases, sequences of thyroid hormoneresponsive elements (TRE) have been identified in the promoter or intronic regions of thyroid hormonedependent brain genes. Among these, myelin basic protein (Farsetti et al., 1992), the Purkinje cell-specific gene (PCP2; Zou et al., 1994), the calmodulin-binding and PKC substrate RC3 (Martinez de Arrieta et al., 1999), prostaglandin D2 synthetase (Garcı´a-Ferna´ndez et al., 1998; White et al., 1997), the transcription factor Hairless (Thompson, 1996), the neuronal cell adhesion

Thyroid Hormones and Brain Development

molecule (NCAM; Iglesias et al., 1996), and the early response gene NGFI-A (Ghorbel et al., 1999). However, there is no final proof that thyroid hormone, in vivo, regulates these genes through interaction with these sites and the physiological significance of the TRE sequences is not really known. Expression of other genes is regulated at the levels of mRNA stability (acetyl cholinesterase), protein translation (MAP2; Silva and Rudas, 1990), or mRNA splicing (Tau; Aniello et al., 1991a). Regulation of splicing might be due to a primary action on the transcription of splicing regulators (Cuadrado et al., 2002).

63.7 Epidemiological and Clinical Aspects Causes of thyroid hormone deficiency during development are iodine deficiency, congenital hypothyroidism, maternal and/or fetal hypothyroidism, and maternal hypothyroxinemia (Figure 4). In addition, defects of thyroid hormone signaling, such as mutations of TRb, and thyroid hormone transporters cause various degrees of impairment in brain function. 63.7.1 Iodine Deficiency Disorders – Endemic Cretinism Iodine is necessary as an integral component of thyroid hormone. Daily adult needs are of the order of 150–200 mg, and even more during pregnancy and lactation (Berbel et al., 2007; Zimmermann, 2007). The thyroid gland has developed efficient mechanisms for concentrating iodine from the blood and keeping a large store of thyroid hormone in the form of iodinated thyroglobulin. There are also efficient autoregulatory mechanisms of thyroidal adaptation to low iodine intake that tend to minimize the consequences of iodine deficiency. Nevertheless, iodine deficiency causes a wide spectrum of abnormalities collectively known as iodine deficiency disorders (Maberly, 1994). Among these are a high incidence of abortions and stillbirths, increased perinatal and infant mortalities, neonatal goiter and neonatal hypothyroidism, various degrees of psychomotor and mental defects, and cretinism. Early studies in iodine-deficient areas described two forms of cretinism – neurological and myxedematous, respectively (McCarrison, 1917). Neurological cretinism, first differentiated as a separate clinical entity by McCarrison in the Himalayas, and later on, in Papua-New Guinea, is characterized by severe

2019

mental retardation, deaf-mutism, and a striato-pallidal disorder with spastic diplegia affecting the lower limbs (DeLong et al., 1985). The clinical picture suggests damage to the striatum and the cerebral cortex during the second trimester of pregnancy (Figure 4). The thyroid gland is normal and there are no physical signs of hypothyroidism. Also, circulating thyroid hormone concentrations, with low T4 and normal T3, are similar to the noncretin population. When given sufficient iodine, their circulating T4 and T3 concentrations become normal because there is no primary thyroid failure. On the other hand, myxedematous cretins (Thilly et al., 1986) are also mentally retarded but not as severely as neurological cretins, with signs of neurological involvement observed only in a minority of cases. They have physical signs of hypothyroidism, such as short stature, craniofacial abnormalities, and poor sexual development. Iodine administration to the mothers late in pregnancy is very effective in preventing the myxedematous form, but totally ineffective in the neurological type. The only way to prevent the latter is by administering iodine before pregnancy to the prospective mothers or early in gestation (Pharoah et al., 1971; Pharoah and Connolly, 1991). Myxedematous cretins have an impaired thyroid function and are, in many respects, similar to untreated congenitally hypothyroid patients present in iodine-sufficient areas. In some affected regions, there is destruction of the thyroid glands due to the combination of low iodine supply, high intake of goitrogens in the diet, and selenium deficiency (Contempre´ et al., 1995, 1997). The pathogenesis of neurological cretinism was difficult to understand until the mid-1980s, because the affected children were not hypothyroid, and early postnatal administration of iodine or treatment with thyroid hormone were ineffective. In the light of many clinical and biochemical studies, the pathogenesis of these two syndromes can be explained on the basis the relative roles of the maternal, and the fetal and infant, thyroid hormones. Neurological cretinism is due to the profound hypothyroxinemia of the pregnant women caused by severe iodine deficiency, especially during the first half of pregnancy (Figure 4), whereas myxedematous cretinism is due to failure of the fetal, and infant, thyroid during the last trimester of pregnancy and postnatal period. 63.7.2

Congenital Hypothyroidism

Congenital failure of the thyroid gland occurs in about 1 in 3000–4000 newborns (for a review see

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Thyroid Hormones and Brain Development

(a)

(b)

(c)

Maternal thyroid hormone Increasing type 2 deiodinase activity, and T3 in cerebral cortex Nuclear receptors in brain, liver, lung, kidney …

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T3 in brain nuclear receptor Thyroid gland

Thyroid hormone secretion

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Striatum Neocortex Cerebellum, dentate gyrus granular cells Cochlea Myelination Glial cell proliferation Synapse formation Axon and dendrite sprouting Neuronal migration Neuronal proliferation Early embryogenesis 0

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Figure 4 Main milestones of human fetal and neonatal development in relation to thyroid hormones. The stages of fetal development are in weeks and of postnatal development in years. The equivalent stage for birth of the rat is shown by the vertical bar, corresponding to the 20 th week. The upper part of the diagram shows important landmarks in thyroid development. Maternal thyroid hormones are available throughout pregnancy, but the amount reaching the fetal tissues may be limited by high expression of D3 from early embryogenesis. Thyroid gland organogenesis occurs during the first trimester, but secretion of thyroid hormones does not occur until the 20 th week. Before this, D2 is detected in cerebral cortex, from the begining of the second trimester, in parallel to the appearance of nuclear receptors in brain, and T3. Therefore it is likely that the origin of brain T3 at these stages maternally derived T4. In the lower half of the diagram is shown the timing of maturation of brain regions and developmental processes under thyroid hormone influence. In the upper part of the figure is represented the approximate timing of insults for (a) neurological cretinism and maternal hypothyroxinemia, (b) prematurity, and (c) congenital hypothyroidism and myxedematous cretinism. Adapted from Bernal J (2007) Thyroid hormone receptors in brain development and function. Nature Clinical Practice Endocrinology and Metabolism 3: 249–259.

Delange (1997)). Because it is the most frequent preventable cause of mental retardation in industrialized countries, neonatal screening based on thyroidstimulating hormone (TSH) and/or T4 determinations in heel blood is widely performed. The most common causes of permanent congenital hypothyroidism are thyroid dysgenesis, mainly ectopic thyroid gland and agenesia, and inborn errors in thyroid hormone biosynthesis. A family with a truncated TSH receptor has also been described (Tiosano et al., 1999). A small percentage of thyroid dysgenesis is associated with mutations of genes involved in thyroid embryogenesis (Trueba et al., 2005), but the

great majority of cases are due to non-Mendelian mechanisms, with several genes involved (Deladoey et al., 2007). Before systematic screening was available, the diagnosis of congenital hypothyroidism was usually delayed for months or years. Affected children had mental retardation, failure to thrive, and short stature. Thyroid hormone treatment was usually administered too late to prevent brain damage. Fortunately, systematic screening has made possible early diagnosis and treatment, thus preventing mental retardation effectively. Despite this, some affected individuals may remain with neuropsychological deficits, such as

Thyroid Hormones and Brain Development

learning disabilities and disturbance of fine-motor coordination, indicative of minimal brain damage. The success of thyroid hormone treatment depends on the severity, onset, and duration of the disease. It is very important, therefore, to identify the children who may be at risk of having neurological sequelae even with early diagnosis and treatment. This is accomplished by the estimation of bone maturation and plasma T4 levels at diagnosis. These children may require a substantially higher replacement dose of T4 than moderate cases (Dubois et al., 1996). 63.7.3 Maternal Hypothyroidism and Maternal Hypothyroxinemia Congenitally hypothyroid babies, even those with total thyroid agenesis, do not have the severe neurological deficits of neurological cretinism and early treatment with thyroid hormone is effective in preventing mental deficiency. Maternal thyroid hormones cross the placenta and protect the fetal brain until birth (Morreale de Escobar et al., 2000). It is estimated that up to 50% of fetal blood T4 at term is of maternal origin (Vulsma et al., 1989). In cases of severe maternal and fetal hypothyroidism due to Pit-1 deficiency (de Zegher et al., 1995) or to high titers of thyroid-stimulation-blocking antibodies (Blizzard et al., 1960; Yasuda et al., 1999), circulating thyroid hormones are very low in the mother, and in the infant. Children suffer from permanent sensorioneural deafness and irreversible neuromotor development despite early postnatal treatment with thyroid hormone, thus resembling neurological cretinism. On the other hand, even when the fetal thyroid is normal, maternal hypothyroidism has harmful effects on brain development of the progeny (Man and Serunian, 1976; Haddow et al., 1999). Children born of mothers with high TSH during the second trimester of pregnancy had impaired performance at ages 7–9 on tests that measure intelligence, attention, language, and school and visual-motor performance. On the whole, the data suggested a reduction of about 4 points in the IQ of children born from hypothyroid mothers (Haddow et al., 1999). These studies raise the question of whether universal screening of pregnant women for high TSH during early pregnancy is warranted. Moreover, it has become increasingly clear that not only frank hypothyroidism, but maternal hypothyroxinemia may affect brain development. Thus, several studies have shown a higher incidence of neurological alterations in children from hypothyroxinemic mothers

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(Pop et al., 1999; Kooistra et al., 2006). Vermiglio et al. found that hypothyroxinemia is associated with increased incidence of attention-deficit hyperactivity disorder (ADHD; Vermiglio et al., 2004). Hypothyroxinemia is a situation with low T4 and normal TSH. Therefore, TSH screening would only detect a fraction of the population at risk (Morreale de Escobar and Escobar del Rey, 1999; Morreale de Escobar et al., 2000).The incidence of hypothyroidism in pregnant women is around 2.5% but hypothyroxinemia is more prevalent – up to 30% of normal pregnancies in some populations (Glinoer, 1997). This is usually due to mild iodine deficiency (Utiger, 1999) which maintains a situation of peripheral euthyroidism, with normal TSH, by compensatory mechanisms, including increased D2 activity, and preferential thyroidal secretion of T3. For these reasons iodine supplementation of women considering conception and during pregnancy and lactation is warranted (Berbel et al., 2007). 63.7.4 The Hypothyroxinemia of Prematurity Premature babies often present with transient hypothyroxinemia lasting several weeks (Fisher, 1998; Reuss et al., 1997). Hypothyroxinemia occurs in around 85% of preterm babies and is caused by several factors, including mainly the interruption of the maternal supply of T4 to the fetus, at a stage of development when the maternal T4 should contribute an important fraction of normal fetal plasma T4. For the fetus at term, this fraction has been estimated to be 30–50% (Vulsma et al., 1989), but in earlier periods, it is likely to be much higher given the immaturity of the fetal thyroid gland (van den Hove et al., 1999). It is difficult to consider the hypothyroxinemia of prematurity as a physiological condition (due to the immaturity of the hypothalamic–pituitary–thyroid axis) because in utero the fetus would have been exposed to a higher circulating T4. Circulating total T4 and FT4 concentrations are lower in preterm neonates than in fetuses of comparable age still in utero (Morreale de Escobar and Ares, 1998; Thorpe-Beeston et al., 1991; Williams et al., 2004). As mentioned in earlier sections of this chapter, several lines of evidence support the view that the fetal brain is a target of thyroid hormone at least from the second trimester of pregnancy (Bernal, 2007). Therefore, the hypothyroxinemia of prematurity may have clinical consequences and several studies have shown that it may represent an independent risk

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Thyroid Hormones and Brain Development

of subsequent neurological and mental developmental problems (Den Ouden et al., 1996), increased risk of cerebral palsy (Reuss et al., 1996), and white matter damage (Levinton et al., 1999). The issue of whether preterm babies should be treated with thyroid hormone is not settled. There is some evidence that thyroxine treatment may be beneficial, especially in premature babies born before the 27th week of gestation, but not later (van Wassenaer et al., 1997). In these studies, however, administration of T4 in a single daily dose may have suppressed TSH as there was a decrease of serum T3 (van Wassenaer et al., 1998). Additional studies are going on to establish whether T4 treatment is warranted, what could be the optimal dose of T4, and whether or not T3 should also be administered (La Gamma et al., 2006). 63.7.5 Thyroid Hormone Transporter Mutations So far, mutations have only been identified in MCT8, a 12-transmembrane protein encoded by a gene located in chromosome X. They were first described in children by the groups of Refetoff (Dumitrescu et al., 2004) and de Visser (Friesema et al., 2004). Additional cases were reported subsequently (Gruters, 2007; Holden et al., 2005; Namba et al., 2008). The affected patients have X-linked mental retardation with severe developmental delay and neurological damage together with an unusually altered pattern of thyroid hormone levels in blood. Total and free T4 and rT3 were low, whereas total and free T3 were elevated. TSH was either moderately elevated or normal. The neurological syndrome consists of global developmental delay, rotary nystagmus, impaired gaze and hearing, dystonic movements, and severe proximal hypotonia with poor head control that progressively develops into spastic quadriplegia. A syndrome of paroxysmal dyskinesia was also described in some of the patients (Brockmann et al., 2005). It was also recognized that the Allan–Herndon–Dudley syndrome (OMIM 300523) is due to MCT8 mutations (Schwartz et al., 2005). The neurological syndrome is postulated to be due to defective T3 transport to neurons during critical periods of development, similar to neurological cretinism. There are not only some similarities, but also differences, with the latter (Bernal, 2005b; Heuer, 2007). It is, therefore, unclear whether the neurological syndrome is due to deficient T3 transport to neurons, or to another factor, including a still

unrecognized T3-independent activity of MCT8, or deficient transport of another metabolite. MCT8 KO mice have been generated (Dumitrescu et al., 2006; Trajkovic et al., 2007). As in patients, the mct8/y mice have elevated circulating T3 and reduced T4 and rT3. However, they have minimal, if any, brain impairment and only a small decrease in the expression of some T3 target genes. The altered circulating thyroid hormone levels are due to increased T4 and rT3 degradation and increased T3 peripheral production combined with decreased degradation. The decreased T3 degradation is due to restricted entry of T3 to D3-expressing cells, such as neurons. The subsequent increase of T3 increases D1 activity in the liver, causing an increased degradation of rT3 and increased conversion of T4 to T3. In addition, the reduction in T4 availability to the astrocytes increases D2, contributing to increased production of T3 from T4. Therefore, there are two important features of this syndrome: one is the concomitant increase in the activity of the two deiodinases, D1 and D2. The second is the coexistence of hyperthyroid (liver) and hypothyroid (brain) tissues. Even within the brain, the presence of alternative transporters in some cells may expose these cells to excessive T3. 63.7.6 Triiodothyronine Receptor Mutations So far, mutations of the thyroid hormone receptor in humans have only been identified in TRb, and cause the syndrome of resistance to thyroid hormone (RTH) (Refetoff and Dumitrescu, 2007). The main characteristic of this syndrome is the dissociation of thyroid hormone concentrations in blood with biological endpoints of thyroid hormone action. Total and free thyroid hormones are elevated but TSH is not suppressed. The mutant TRb may cause learning disabilities, reduced IQ , and an increased incidence of ADHDs. TRb KO, or knockin (KI) mice expressing TRb mutations, are a good model of RTH (Forrest et al., 1996). In addition, the phenotypic analysis of these mice has disclosed the important role of TRb in maturation of somatosensory systems. TRb mutant mice have deafness and impaired color vision, due to altered maturation of cochlear hairy cells and retinal photoreceptors ( Jones et al., 2003; Roberts et al., 2006). Mice expressing a mutant TRb with strong dominant negative properties, had cerebellar abnormalities reminiscent of severe hypothyroidism and neuromotor disability (Hashimoto et al., 2001).

Thyroid Hormones and Brain Development

TRa gene mutations have not been found in humans. It is likely that mutations of this gene, if they exist, do not cause significant alterations of the hypothalamic–pituitary–thyroid axis, and therefore, the clinical picture would not be recognized as a disorder of the thyroid system. TRa KO and KI mice have been produced in an effort to define what would be the consequences of TRa deletion or mutations (Flamant and Samarut, 2003). TRa1 KO mice do not present the typical alterations of brain structure and gene expression of the hypothyroid animals, because deletion of the receptor is not equivalent to hormonal deprivation (Figure 5). In the absence of the hormone, the receptor (aporeceptor) has hormone-independent activity, either repression or activation of transcription, that leads to a disturbance of the processes normally controlled by thyroid hormones, and to the symptoms of hypothyroidism, especially in the brain (Morte et al., 2002) (Flamant et al., 2002). However, expression of mutant TRa1 with dominant negative activity causes retarded growth (Tinnikov et al., 2002), low cerebral glucose consumption (Itoh et al., 2001), features of hypothyroidism, including retarded cerebellar development and neuromotor impairment in developing animals (Venero et al., 2005; Quignodon et al., 2007b), and a profound anxiety in adult animals, which was ameliorated by T3 treatment. The consequences of TRa1 mutations may also be heterogeneous depending on the mutation (Sjogren et al., 2007). Do unliganded receptors play a physiological role during development because of their transcriptional activity? Since the receptors are expressed before the onset of thyroid gland secretion, occupancy of receptors during development would be dependent, as explained above, on the maternal hormones and the activity of deiodinases. In human fetuses (Kester et al., 2004), it was demonstrated that, during the second trimester, the cerebral cortex expresses D2 and T3 concentration increases. However, at the same stages, the cerebellum expresses mainly D3, and T3 concentration is very low. Since at these stages the receptor is present, these findings suggest that the unliganded receptor may be relevant for fetal cerebellar development. Evidence for a role of unliganded receptors can be found in studies on amphibian metamorphosis (Sato et al., 2007), or in the development of the inner ear in mice (Winter et al., 2007). In the latter, the interplay between repression by TRa1 and rising concentrations of T3 are essential components of the developmental timing process allowing the orderly expression of ion channels.

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Wild-type mice P21

P11

EGL

IGL

Intact

Hypo

Intact TRα1–/– mice P21

P11 EGL

IGL

Intact

Intact

Hypo

Figure 5 Effects of hypothyroidism in the cerebellum of wild-type mice and in mice with deletion of thyroid hormone receptor alpha 1 subtype (TRa1). Sections of the cerebellar cortex stained with toluidine blue showing the external (EGL) and internal granular layers (IGL), in wild-type mice and in TRa1 mutant mice, at postnatal days 11 (P11) and 21 (P21). In the wild-type mice (upper panel), migration of granular cells to the IGL is completed in intact animals, but not in hypothyroid animals (Hypo), in which the EGL persists at P21. Deletion of TRa1 (lower panel) had no effect on cerebellar structure at P11 or P21, indicating that TRa1 is dispensable for granular cell migration. However, in clear contrast to wild-type animals, hypothyroidism had no effect on the TRa1-deficient mice. This indicates that the effect of hypothyroidism is due to an interfering action of TRa1. Adapted from Morte B, Manzano J, Scanlan T, Vennstrom B, and Bernal J (2002) Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proceedings of the National Academy of Sciences of the United States of America 99: 3985–3989.

63.8 Conclusions and Perspectives Thyroid hormone deficiency in developing mammals, including humans, may lead to severe morphological and functional alterations of the CNS. The brain is a very important target of the thyroid hormone, but its complexity has precluded an

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Thyroid Hormones and Brain Development

understanding of the mechanisms of action of thyroid hormones. Most of these actions are exerted through the nuclear receptors, and regulation of gene expression. Extragenomic effects of thyroid hormones are increasingly being recognized, but how they contribute to their action in the brain is still unknown. New findings have broadened our perspectives on the action of thyroid hormone in the brain, and have identified new clinical situations. The physiological role of the plasma membrane transporters for thyroid hormone has received solid support with the finding that transporter mutations lead to a severe neurological syndrome. The analysis of receptor mutant mice has led to new concepts, such as the role of unliganded receptors in the pathogenesis of the hypothyroid phenotype. Thus, the paradox that the absence of the receptor was not equivalent to the absence of the hormone is explained by the harmful activity of the unliganded receptor. This hypothesis has received further support with the observations that expression of mutant receptors with dominant negative activity lead to the typical alterations of severe hypothyroidism. Important issues for the future include the need for more detailed identification of the genes regulated by thyroid hormones in brain during fetal development and the exact role of the maternal hormones in this process, the pathogenesis of the neurological syndrome due to transporter mutations, and whether the unliganded receptors have a role during development.

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Biographical Sketch

Juan Bernal, MD, PhD, is professor of Research, Consejo Superior de Investigaciones Cientı´ficas (High Council for Scientific Research, CSIC), Autonomous University of Madrid, and the Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain. His MD degree was awarded from the University of Seville, Spain (1969), and his PhD degree was from the University of Madrid (1974). His postdoctoral work (1974–77) was at the University of Chicago, IL, USA. He has been group leader at the Biomedical Research Institute of the CSIC, Madrid since 1977. He was a visiting scientist at the Department of Endocrinology of the University of Helsinki, Finland (1981–82), the Department of Molecular Biology of The Scripps Research Institute, La Jolla, CA, USA (1988–89 and 1993–94), and the University of Pisa, Italy (2004). He was director of the Biomedical Research Institute (1997–2001) and scientific coordinator of the Biological and Biomedical Division of the Spanish Research Council (2001–04).