Coordinate expression of functionally distinct thyroid hormone receptor α isoforms during neonatal brain development

Abstract

Thyroid hormone receptors (TRs) are nuclear proteins that regulate gene expression through interactions with specific DNA sequences. It is well known that thyroid hormones have critical functions in the control of normal brain development. In the rat brain, at least three mRNA species are generated by differential processing of the TRα transcript. Only one of the isoforms, TRα-1, is a transcriptional activator, while the regulatory roles of the carboxyterminal variants TRa-2 and TRα-2v remain unclear. In this study we have used polymerase chain reaction amplification of total RNA to compare TRα-1, TRα-2, and TRα-2v mRNA levels in the brainstem, cerebellum, cerebrum, midbrain, and olfactory bulbs of developing neonatal brains in rats. RNA was collected 5, 10, 15, 20, and 25 days after birth from both normal and hypothyroid animals. Coordinate expression of all three isoforms was observed in most tissues during development, with TRα-2 generally maintaining the highest level of expression, and TRα-1 the lowest. In hypothyroid tissues, TRα-1 message was generally increased, while TRα-2 was not. To explore the possible roles of the TRα isoforms, we have compared their DNA-binding activities. We report that compared to TRα-1, the carboxyterminal variants TRα-2 and TRα-2v show different binding patterns with a thyroid hormone response element, suggesting that they bind only poorly as monomers. The varying ratios of the TRα isoform expression together with their distinct binding patterns and reported represser functions suggest that TRα isoforms have important roles during brain development and function, and may serve to fine-tune the biological responses to thyroid hormone Copyright © 1991 by The Endocrine Society.