ReviewMultigenic control of thyroid hormone functions in the nervous system
Introduction
It has long been evident from human cretinism that TH is necessary for brain development (Osler, 1897, Gesell et al., 1936). The neurological retardation arising in cretinism results from TH insufficiency during critical periods of neuronal differentiation. TH insufficiency can result from impairment of the thyroid gland (congenital hypothyroidism) or from a lack of the dietary iodine necessary for biosynthesis of TH. Newborn screening and hormonal replacement have greatly reduced the occurrence of mental retardation in congenital hypothyroidism (Rovet and Daneman, 2003). Iodine deficiency remains a widespread cause of mental retardation in a number of developing countries (Delong et al., 1985, Delange, 2001).
The symptoms of cretinism are diverse and suggest a role for TH in learning, language ability, memory, motor control and sensory function. Recent findings indicate that the spectrum of functions of TH in the mammalian nervous system is wider than may have been anticipated from general observations of cretinism and include, for example, a key role in colour vision (Ng et al., 2001a). This remarkable breadth of functions raises an obvious question: how can this hormone elicit so many different responses? Moreover, the responses in a given tissue change as development progresses such that a lack of TH produces different defects in the adult than in the fetus or infant. The question therefore becomes more complex: what determines the temporal as well as the cellular specificity of TH actions within the nervous system?
Genetic studies of model species and of human disease have pointed to some answers by identifying a number of genes that mediate or modify TH action in neural target tissues. Nervous system phenotypes have been identified in mice with mutations in the TH receptor α and β genes and in genes encoding deiodinase enzymes that metabolize TH (Forrest et al., 1996, Bernal, 2007, Galton et al., 2007). Human neurological defects have been associated with mutations in the TH receptor β gene (Refetoff et al., 1993, Chatterjee and Beck-Peccoz, 2001) and in the MCT8 gene that encodes a TH transporter (Dumitrescu et al., 2004, Friesema et al., 2004). Genetic defects that interfere with TH action at any level in the target tissue may potentially cause neurological phenotypes, as shall be discussed (Fig. 1 and Table 1).
Although it is common knowledge that TH is generally required by the nervous system, our understanding of how this hormone elicits its functions is far from complete. This article reviews a number of functions of TH in the nervous system and the emerging view of the multigenic mechanisms that determine these actions. Evidence suggests that the selective cooperation of a limited number of genes encoding receptors, deiodinases and other components determines the nature, time and place of TH actions in the nervous system.
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Early experimental studies
Pioneering investigations into the underlying actions of TH in the brain were performed by Eayrs (Eayrs and Taylor, 1951, Eayrs, 1966) and Legrand (Legrand, 1984) beginning half a century ago. These studies in model species, mainly the rat, revealed several features that are still pertinent to research today. (i) It was evident that TH has multiple different functions in the brain. Thus, hypothyroidism delayed cell migration, outgrowth of neuronal processes, synaptogenesis and myelin formation
TH action at the cellular level
The nuclear TH receptor (TR) is a ligand-regulated transcription factor and has a central role in transducing the hormonal signal into a cellular response (Sap et al., 1986, Weinberger et al., 1986, Tata, 2006). The transcriptional activity of the TR is not the main focus of this article but a few features relevant to the nervous system are mentioned here.
The TR can act as a ligand-regulated repressor or activator on different genes such that target genes fall into both positive (induced) and
TH availability in the nervous system
TR activity can be controlled at several steps preceding its interaction with a target gene. The amount of TH ligand available to neural tissues is governed initially by the activity of the thyroid gland and by the iodine present in the diet. The thyroid gland releases two major forms of TH, thyroxine (3,5,3′,5′-tetraiodothyronine, T4) and 3,5,3′-triiodothyronine (T3) (Fig. 1). T3 is the main active form of hormone that binds the TR although T4 is more abundant than T3 in serum. T3 is also
Thyroid hormone receptors in the nervous system
Functions in the nervous system have been identified for both the Thrb and Thra receptor genes (Table 2). Vertebrate species express three conserved TR isoforms and their functions have been demonstrated by targeted deletions (knockout) and change-of-function (knock-in) mutations in mice (discussed below). Thrb encodes two major isoforms, TRβ1 and TRβ2, whereas Thra encodes a single T3 receptor, TRα1. Other truncated or variant TR products have been found but only in isolated species (Harvey et
Thrb functions
The Thrb gene serves a prominent role in sensory systems. Thrb mutations cause deafness in mice (Forrest et al., 1996, Griffith et al., 2002, Shibusawa et al., 2003) and are associated with hearing loss in humans (Brucker-Davis et al., 1996). Thrb-deficiency or hypothyroidism in rodents retards the maturation of many cochlear cell types including the sensory hair cells and deforms the tectorial membrane which mediates transduction of sound (Deol, 1976, Uziel, 1986). Thrb-deficiency retards the
Thra functions
To date, inherited mutations in the human THRA gene have not been reported. In mice, Thra mutations produce a different spectrum of phenotypes than do Thrb mutations and these include defects in behaviour and synaptic function. A Thra knock-in mutation that over-expresses a dominant negative TRα1 causes anxiety-like symptoms and learning defects together with abnormalities in hippocampal inhibitory neurons of the GABA (γ-amino butyric acid) class (Venero et al., 2005). Thra deletion also causes
Thra and Thrb cooperative functions
Cooperation between the Thra and Thrb genes in the nervous system is likely to be more widespread than is evident from the limited studies described to date. Cooperation may occur at several levels. First, in many scenarios, an individual cell type may express some amount of both TRα1 and TRβ, such that both TR isoforms can contribute to the joint regulation the same target genes. Alternatively, in a more complex scenario, TRα1 and TRβ may act in distinct cell types in a tissue or organ to
TH and the formation of neuronal connections
Eayrs and Legrand showed that a major role of TH in the brain is to promote the growth of axons and dendrites and the formation of synaptic densities. These findings have renewed relevance today in the light of studies of the underlying genes.
The cerebellum, the subject of many of these studies, represents a classical model of TH action in the brain (Fig. 4). The cerebellar granule cells proliferate after birth in the external granular layer during the first two postnatal weeks. The granule
Axonal and dendritic outgrowth and the neuronal cytoskeleton
TH regulates axonal and dendritic outgrowth largely through the growth cone, the motile tip of growing axons. The behaviour of the growth cone is driven by dynamic reorganization of actin filaments and microtubules by signaling pathways linked to guidance cue receptors (Dickson, 2002). Microtubule assembly is promoted by microtubule-associated proteins (MAPs), including Tau, which promote polymerization of the α,β tubulin dimer and by interactions with other cytoskeletal and extracellular
Synaptic activity and glucose utilization
Maturation of the mammalian brain is accompanied by profound increases in local rates of glucose utilization (Kennedy et al., 1982). In rats made hypothyroid at birth and studied later in adulthood, rates of cerebral glucose utilization are markedly depressed with the greatest decreases occurring in the cerebral cortex and auditory pathways (Dow-Edwards et al., 1986).
Glucose is the sole nutrient used by the brain to produce the energy for synaptic activity. There is a close correlation between
TH and adult brain function
TH deficiency has different consequences in adult and geriatric life than in early development. TH abnormalities in adulthood produce milder symptoms but these can have a pronounced influence on mood and anxiety. Adult abnormalities, unlike those in development, are generally reversible. The association of TH dysfunction and mood disturbance is well recognized although its prevalence is not established (Simon et al., 2002, Bunevicius et al., 2005, Jorde et al., 2006). Nonetheless, since the
Concluding comments
Genetic, cellular and physiological studies have made fascinating progress in elucidating specific functions of TH in the nervous system. It is also interesting to reflect on these functions as a whole rather than as separate parts given that, in life, TH acts in the context of the whole organism.
It is noteworthy that although mice lacking all nuclear TH receptors are runted, they retain vital bodily functions and near normal longevity (Göthe et al., 1999). These observations point to TH as a
Acknowledgement
This work was supported by the intramural research program at NIDDK/NIH. We thank Jack Robbins for many comments on the subject of this review.
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