TOP ＞ シンポジウム

シンポジウム The mechanisms of thryoid hormone action 1S2-1 Thyroid hormone and the nervous system Forrest Douglas1，Liu Hong1，Huang Jeff1，Wu Xuefeng1，Swaroop Anand2，Ng Lily1，Fu Yulong1 1NIDDK, National Institutes of Health，2National Eye Institute Thyroid hormone（T3）promotes diverse functions in the development and function of the nervous system. This is evident from the mental retardation that can result from defects caused for example, by congenital hypothyroidism or endemic iodine deficiency. Although the requirement for T3 is well-recognized, less is known of the underlying cellular functions that T3 regulates and how T3 acts at appropriate stages of development. We have addressed these questions by investigation of thyroid hormone receptors（TR）, which act as ligand-regulated transcription factors. Two genes, Thra and Thrb, encode three TR isoforms, TRa1, TRb1 and TRb2 which serve a variety of functions in the nervous system. Mutagenesis in mice and observations in human patients indicate that the Thrb gene is important in sensory systems. In the mouse retina, TRb2 is unexpectedly critical for generating diversity in cone photoreceptors, which mediate colour vision. TRb2-deficiency results in a form of blue monochromacy with the presence of blue（or S）cones for response to short wave light but lack of green（or M）cones for response to medium/long wave light. Evidence indicates further developmental plasticity in photoreceptor precursor cells that extends to rods, the photoreceptors for vision in dim light. Differential expression of two factors, TRb2 and Nrl, a leucine zipper transcription factor, can direct common precursors to three photoreceptor outcomes：M cone, S cone or rod. Cones are also sensitive to the level of T3 at immature stages, such that excessive T3 acting on TRb2 eliminates cones by apoptotsis. Cone survival is safeguarded by type 3 deiodinase, a thyroid hormone-degrading enzyme. The findings suggest that in neurodevelopment, cell-specific responses to T3 are determined by specific TR isoforms acting in cooperation with ligand-metabolizing deiodinases in the neural tissue environment. 1S2-2 Neuroendocrine Regulation of Iodothyronine Deiodinases Araki Osamu，Murakami Masami Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine Thyroid hormones play important roles in normal brain development and function. Thyroxine（T4）, which is a major secretory product of the thyroid gland, needs to be converted to 3, 5, 3’-triiodothyronine（T3）by iodothyronine deiodinase to exert its biological activity. Two different isozymes, type 1（D1）and type2（D2）iodothyronine deiodinase, catalyze T4 activation. D1 is mainly present in thyroid gland, liver, and kidney, whereas D2 is present in brain, anterior pituitary, brown fat, and pineal gland, in the rat. D2 activity increases in the hypothyroid state and plays a critical role in providing local intracellular T3. Type 3 iodothyronine deiodinase（D3）inactivates T4 and T3 to 3,3’,5’-triiodothyronine（rT3）and 3,3’-diiodothyronine（T2）, respectively. Iodothyronine deiodinases play important roles in the regulation of cell-specific thyroid hormone action. In the rat pineal gland, D2 shows nocturnal increase by a beta-adrenergic mechanism. Indeed, cAMP response elements have been demonstrated in D2 gene promoter, TSH receptor-cAMP-mediated expression of D2 in human thyroid gland and osteoblast, and rat brown adipose tissue has been reported. In the central nervous system, D2 is present in astrocytes, whereas D3 is predominantly expressed in neurons. In humans, D2 and D3 have been demonstrated in normal brain tissues and brain tumors. We identified that D2 is highly expressed in anaplastic oligodendroglioma tissue. Among the glial cells, it is well known that thyroid hormones play important roles in the development of oligodendrocytes. Increased T3 production by D2 in oligodendroglioma may play roles related to the functions of thyroid hormones in oligodendrocytes. To elucidate the deiodinase-regulated thyroid hormone action in ologodendroglioma cells, we studied the expression and regulation of deiodinases in human oligodendroglioma（HOG）cells. D2 was expressed in HOG cells, and its expression was increased by beta-adrenergic stimulation and inhibited by glucocorticoid. Hypothyroid state increased D2 expression in HOG cells, and thyroid hormones decreased D2 activity through the ubiquitin-proteasome pathway. Increased T3 production by D2 in HOG cells may play pathophysiological roles in oligodendroglioma and oligodendrocytes-specific thyroid hormone action. 1S2-3 Attenuation of local thyroid hormone signaling due to reduction of DIO2：SAMP8 mouse as an unique animal model of developmental anomalies and later-onset cognitive deficits Tashiro Tomoko Dept. Chemistry ＆ Biological Science, Sch. Science ＆ Engineering, Aoyama Gakuin Univ. Thyroid hormone（TH）regulates many aspects of neural network formation including neural cell migration, synaptogenesis, and myelination. Studies using rodent models show that perinatal hypothyroidism strongly affects the development of the GABAergic system, resulting in attenuation of inhibitory neurotransmission. While the number of total GABAergic neurons was not altered, subpopulations expressing parvalbumin and neuropeptide Y（NPY）were preferentially reduced in the hippocampus of hypothyroid rats which could be rescued by TH replacement after birth. A key molecule in post-synaptic switching of GABA action from excitatory to inhibitory, the neuron-specific K+/Cl- co-transporter（KCC2）, was also TH-responsive. The senescence-accelerated mouse prone 8（SAMP8）is a spontaneous model of neurodegeneration exhibiting age-related cognitive deficits with little physical impairment. Before the onset of cognitive impairment, young SAMP8 mice show signs of developmental anomalies such as marked hyperactivity and reduced anxiety. While exploring the possible involvement of the TH system, we found a significant reduction of the TH-activating enzyme, type 2 deiodinase（DIO2）, in the hippocampus and the cerebral cortex of SAMP8 compared with the normally-aging SAM resistant 1（SAMR1）starting from the onset of its expression in the early postnatal weeks. Attenuation of TH signaling was confirmed by down-regulation of TH-responsive genes in SAMP8 including KCC2. Although distribution of total GABAergic neurons was similar in both strains, NPY-positive neurons in the SAMP8 hippocampus were reduced by 22-30%. Electrophysiological comparison of hippocampal slices at 4 weeks revealed that epileptiform activity induced by high frequency stimulation lasted 4-times longer in SAMP8 compared with SAMR1, indicating dysregulation of excitability. The results suggest that local attenuation of thyroid hormone signaling without changes in plasma TH levels may lead to behavioral and cognitive disorders.