REGULATION OF NEURONAL THYROID-HORMONE RECEPTOR ALPHA(1) MESSENGER-RNA BY HYDROCORTISONE, THYROID-HORMONE AND RETINOIC ACID

The regulation of thyroid hormone receptor alpha(1) (TR alpha(1)) mRNA by hydrocortisone (HC), thyroid hormone (T-3) and retinoic acid (RA) has been studied in mixed and neuronal primary cultures of cells disso ciated 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 mu M HC in both mixed and neuronal-enriched cultures. The regulation of T R alpha(1) mRNA by HC appears to be mainly limited to neurons. This co nclusion 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, o ligodendroglia and astroglia). Second, the stimulation reaches a peak at 13 days in mixed-cell cultures, an age at which neurons but not gli a differentiate. In most cases, neither T-3 (20 nM) nor RA (10(-7) M) stimulated an increase in TR alpha(1) mRNA steady-state levels. The ex ception was that RA increased TR alpha(1) mRNA levels at 13 days in cu lture, but at no other stage of development. In both types of cultures , RA and T-3 separately and together produced as much as a complete in hibition of the stimulation by HC. Regulation by T-3, when it occurred , was always negative. The fact that T-3 can strongly repress the indu ction of TR alpha(1) mRNA by HC demonstrates that T-3 can function thr ough negative cooperativity as a potent regulator of its own receptor in brain.