Regulation of neuronal thyroid hormone receptor alpha 1 mRNA by hydrocortisone, thyroid hormone and retinoic acid.

ABSTRACT

The regulation of thyroid hormone receptor alpha 1 (TR alpha 1) mRNA by hydrocortisone (HC), thyroid hormone (T3) and retinoic acid (RA) has been studied in mixed and neuronal primary cultures of cells dissociated from fetal rat cerebra. Steady-state levels of TR alpha 1 mRNA were increased as much as 5-fold at 13 days of development by 0.3 microM HC in both mixed and neuronal-enriched cultures. The regulation of TR alpha 1 mRNA by HC appears to be mainly limited to neurons. This conclusion is based on two observations. First, stimulation by HC occurs in cultures highly enriched in neurons at approximately the same time and extent as that seen in mixed-cell cultures (containing neurons, oligodendroglia and astroglia). Second, the stimulation reaches a peak at 13 days in mixed-cell cultures, an age at which neurons but not glia differentiate. In most cases, neither T3 (20 nM) nor RA (10(-7) M) stimulated an increase in TR alpha 1 mRNA steady-state levels. The exception was that RA increased TR alpha 1 mRNA levels at 13 days in culture, but at no other stage of development. In both types of cultures, RA and T3 separately and together produced as much as a complete inhibition of the stimulation by HC. Regulation by T3, when it occurred, was always negative. The fact that T3 can strongly repress the induction of TR alpha 1 mRNA by HC demonstrates that T3 can function through negative cooperativity as a potent regulator of its own receptor in brain.