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Isoforms during Neonatal Brain DevelopmentLa Jolla Cancer Research Foundation La Jolla, California 92037
Address requests for reprints to: Dr. Magnus Pfahl, La Jolla Cancer Research Foundation, 10901 North Torrey Pines Road, La Jolla, California 92037.
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 TR
transcript. Only one of the isoforms, TR-1, is a transcriptional activator, while the regulatory roles of the carboxyterminal variants TR-2 and TR-2v remain unclear. In this study we have used polymerase chain reaction amplification of total RNA to compare TR-1, TR-2, and TR-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 TR-2 generally maintaining the highest level of expression, and TR-1 the lowest. In hypothyroid tissues, TR-1 message was generally increased, while TR-2 was not. To explore the possible roles of the TR isoforms, we have compared their DNA-binding activities. We report that compared to TR-1, the carboxyterminal variants TR-2 and TR-2v show different binding patterns with a thyroid hormone response element, suggesting that they bind only poorly as monomers. The varying ratios of the TR isoform expression together with their distinct binding patterns and reported repressor functions suggest that TR isoforms have important roles during brain development and function, and may serve to fine-tune the biological responses to thyroid hormone.
FOOTNOTES
This work was supported by NIH Grant DK-35083 (to M.P.).
* Supported by a postdoctoral fellowship from the Tobacco-Related Disease Research Program of the University of California.
Received for publication January 21, 1991. Revision received May 29, 1991. Accepted for publication June 7, 1991.
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