REGULATION OF ACTIN AND TUBULIN GENE-EXPRESSION BY THYROID-HORMONE DURING RAT-BRAIN DEVELOPMENT

In the developing brain the active neurite outgrowth during the early phase of synaptogenesis is associated with a thyroid hormone dependent expression of tubulin and actin. In this study, the molecular mechani sm of thyroid hormone (TH) action on actin and tubulin gene expression in the developing rat brain has been investigated by comparing the st eady state levels of both mRNAs with their respective rates of transcr iption in cerebra from normal and hypothyroid animals. The development al profile of actin as well as tubulin mRNAs in both normal and hypoth yroid brains display a biphasic pattern, increasing progressively duri ng the first week after birth and declining thereafter. However, hypot hyroidism resulted in a significant reduction in the steady state leve ls of both mRNAs during the first postnatal week. During the second an d third weeks, in contrast to their rapid decline in the normal contro ls, the corresponding decrease in the hypothyroid cerebra was retarded and prolonged resulting in their higher levels under TH-deficient con dition. Kinetics of stimulation of actin and tubulin mRNAs in the 5-da y hypothyroid cerebra following injection of the optimal dose of TH (2 00 mu g T-3/100 g body wt.) demonstrated elevation of both mRNAs withi n 1 h indicating a possible role of TH at the transcriptional level. I n vitro transcription experiments by nuclear run off assay unambiguous ly confirmed that actin gene transcription is depressed in the hypothy roid cerebra compared to normal control. This reduced rate of transcri ption could be significantly induced in the hypothyroid cerebra by inc ubation of hypothyroid nuclei with T-3 prior to transcription. In cont rast, except for a reduced transcription in 5-day hypothyroid nuclei, no effect on tubulin gene transcription was evident at any other age. Moreover preincubation of hypothyroid nuclei from all three ages with T; had no stimulatory effect on tubulin gene transcription. Analysis o f age related changes in the rates of transcription of actin and tubul in genes with their corresponding steady state mRNA levels in normal a nd hypothyroid developing brain provides strong evidence that although additional modes of regulation may be operative, transcription repres ents an important level of control for thyroidal regulation of actin g ene expression while tubulin gene expression is primarily regulated at post-transcriptional level.