Thyroid hormone-regulated brain mitochondrial genes revealed by differential cDNA cloning.

Abstract

Thyroid hormone (T3) 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 T3 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 I). The steady state level of all three RNAs was reduced in hypothyroid animals during the postnatal period and T3 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 T3 does not affect the amount of mitochondrial DNA, the results suggest that the effect of T3 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 T3 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. (J. Clin. Invest. 1995. 96:893-899.)

Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.

“…The decrease was avoided by treating the mothers with T4. More recently, VegaNuñez et al (64) have reported that on E-16 there is a 50% reduction in the levels of 16S mRNA (a mitochondrial gene) in the brain of fetuses from MMI-treated rats. This study shows another prenatal effect of goitrogen treatment on the maturation of the CA1 region of the hippocampus.…”

Thyroid hormones in fetal growth and prepartum maturation

“…Mitochondrial contents of total protein and cytochrome c oxidase, a component of the ETC, are reduced by prenatal hypothyroidism in skeletal muscle and liver of fetal and newborn pigs (Herpin et al 1996). Similarly, cerebral cytochrome c oxidase is reduced in hypothyroid rat fetuses without a change in mitochondrial DNA content (Vega-Nunez et al 1995). In addition, in fetal sheep, plasma T 3 concentrations are positively related to adipose tissue expression of the mitochondrial uncoupling proteins 1 and 2 (UCP1 and UCP2), which dissipate the mitochondrial proton gradient and reduce the efficiency of ATP production , Gnanalingham et al 2005.…”

Thyroid Hormone-dependent Gene Expression Program for Xenopus Neural Development

“…Several attempts to isolate T 3 -regulated genes in neonatal rodent brain by differential screening methods have met with limited success (52)(53)(54). Using subtractive hybridization, Munoz et al (52) identified two cDNAs corresponding to T 3 -regulated mRNAs that were decreased only 2-fold in brains from hypothyroid rats; one of these was tentatively identified as myelin basic protein, whereas the other was not identified.…”

“…Two recent attempts identified several mitochondrial genes as T 3 -responsive. Vega-Nunez et al (53) used subtractive hybridization starting with neonatal rat brain mRNA to identify three genes: 12S and 16S rRNAs and cytochrome c oxidase subunit III. Igelesias and colleagues (54) used a whole-genome PCR method to identify NADH dehydrogenase subunit 3 as a T 3 -regulated gene in neonatal mouse brain.…”