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 pe riod results in severe brain damage. However the mechanisms involved a nd the genes specifically regulated by T-3 during brain development ar e largely unknown, By using a subtractive hybridization technique we h ave isolated a number of cDNAs that represented mitochondrial genes (1 2S and 16S rRNAs and cytochrome c oxidase subunit III), The steady sta te level of all three RNAs was reduced in hypothyroid animals during t he postnatal period and T-3 administration restored control levels. Du ring fetal life the level of 16S rRNA was decreased in the brain of hy pothyroid animals, suggesting a prenatal effect of thyroid hormone on brain development, Since T-3 does not affect the amount of mitochondri al DNA, the results suggest that the effect of T-3 is at transcription al 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 a nimals. Hypothyroidism-induced changes in mitochondrial RNAs were foll owed by a concomitant 40% decrease in cytochrome c oxidase activity. T his study shows that Tg is an important regulator of mitochondrial fun ction in the neonatal brain and, more importantly, provides a molecula r basis for the specific action of this hormone in the developing brai n.