Multigenic control of thyroid hormone functions in the nervous system

Abstract

Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by alpha and beta isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity.

Figure 1

An outline of the cellular response to TH. T3 ligand (small red circles) binds a nuclear receptor (TR) that acts as a transcription factor to regulate target gene expression. The TR binds a T3 response element (T3RE) in the gene and its activity is regulated by corepressors (CoR) or coactivators (CoA). TR can bind efficiently to a given T3RE as a homodimer or heterodimer with retinoid X receptor (RXR), or less efficiently as a monomer. T3 is at lower levels than T4 (small grey circles) in the circulation but T3 levels may be amplified by conversion of T4 into T3 by type 2 deiodinase (encoded by Dio2). Ligand may be inactivated by type 3 deiodinase (Dio3) which converts T4 and T3 to rT3 and T2, respectively. T2 and rT3 have minimal biological activity. It should be noted that deiodinases may act in the target cell or in nearby cells through a paracrine-like mode of control. Deiodinases are membrane-associated within the cell. Transporters can control hormone uptake into tissues and communication between cells by hormone transfer.

Figure 2

Auditory deficits caused by deletion of Thrb or Dio2 genes in mice. Comparable elevations in auditory thresholds occur in both strains of mice. Thresholds for a click stimulus assessed by the auditory-evoked brainstem response are ~40 dB sound pressure level (dB SPL) in a wild type mouse. Thresholds in Thrb−/− and Dio2−/− examples shown are 78 and 75 dB SPL, respectively (boxed).

Figure 3

Glucose utilization in the brain of mice carrying TRα or TRβ mutations. Quantitative colour-coded autoradiographs of brain sections from wild type or TRα and TRβ mutant mice. Local rates of glucose utilization established by the deoxyglucose method are encoded in the calibrated color scale at the bottom of the figure. Redrawn (with permission) from Itoh et al Proc. Natl Acad Aci USA, 98: 9913 (2001).

Figure 4

The cerebellum of 14 day old euthyroid and hypothyroid rats stained with antibodies against axon-specific Tau (A) and dendrite-specific MAP2 (B). IGL, internal granular layer, PF, parallel fibres (the axons of granule neurons), PC, Purkinje cell, D, dendrites (of Purkinje cells), ML, molecular layer. Note the shorter parallel fibres and Purkinje cell dendrites in the hypothyroid brain. (Redrawn from Nunez et al, 1989)

Figure 5

A global view of TH functions in the nervous system. TH coordinates the maturation of sensory systems and the central neuronal network in the brain to promote the function of the nervous system as a complete entity.