THYROID HORMONE-REGULATED BRAIN MITOCHONDRIAL GENES REVEALED BY DIFFERENTIAL CDNA CLONING

Thyroid hormone (T-3) plays a critical role in the development of the central nervous system and its deficiency during the early neonatal period results in severe brain damage. However the mechanisms involved and the genes specifically regulated by T-3 during brain development are largely unknown, By using a subtractive hybridization technique we have isolated a number of cDNAs that represented mitochondrial genes (12S and 16S rRNAs and cytochrome c oxidase subunit III), The steady state level of all three RNAs was reduced in hypothyroid animals during the postnatal period and T-3 administration restored control levels. During fetal life the level of 16S rRNA was decreased in the brain of hypothyroid animals, suggesting a prenatal effect of thyroid hormone on brain development, Since T-3 does not affect the amount of mitochondrial DNA, the results suggest that the effect of T-3 is at transcriptional and/or postranscriptional level, In addition, the transcript levels for two nuclear-encoded mitochondrial cytochrome c oxidase subunits: subunits IV and Vic were also decreased in the brains of hypothyroid animals. Hypothyroidism-induced changes in mitochondrial RNAs were followed by a concomitant 40% decrease in cytochrome c oxidase activity. This study shows that Tg is an important regulator of mitochondrial function in the neonatal brain and, more importantly, provides a molecular basis for the specific action of this hormone in the developing brain.