THYROID-HORMONE RESPONSIVENESS IS DEVELOPMENTALLY-REGULATED IN THE RAT SMALL-INTESTINE - A POSSIBLE ROLE FOR THE ALPHA-2 RECEPTOR VARIANT

Thyroid hormone (T-3) alters gene expression through binding to a receptor protein located within the nucleus of target cells. Multiple forms of the T-3 receptor (TR) have been identified and are encoded by the alpha and beta c-erbA genes. We have previously found that TR beta-1 is the major receptor form expressed in the adult rat small intestine, although there are also moderate levels of c-erbA alpha-2, a nonhormone-binding variant that is thought to inhibit T-3 action. In developing rats, we studied the regulation of two small intestinal enterocyte genes previously shown to be T-3 responsive, lactase and 3.0-kilobase intestinal alkaline phosphatase (IAP). Animals were treated with six daily ip injections of either saline (control) or 30 mu g/100 g BW T-3 (T-3 group) and killed at 10 and 25 days of age. Northern analyses of RNA derived from intestinal tissues showed that the magnitude of the T-3-induced changes in lactase and IAP gene expression increased with development. Jejunal 3.0-kilobase IAP messenger RNA (mRNA) levels were unaffected by T-3 at 10 days, but increased by 15-fold at 25 days. Similarly, jejunal lactase mRNA levels were unchanged by T-3 at 10 days, but decreased by 75% at 25 days. Qualitatively similar results were seen in the duodenum and ileum. Studies of TR expression revealed that TR beta-1 mRNA levels were unchanged during the developmental period, whereas the levels of c-erbA alpha-2 decreased by 90% between 5-25 days after birth. These results indicate that the rat small intestine becomes increasingly T-3 responsive during postnatal development. These changes occur in parallel with a decline in c-erbA alpha-2 levels, suggesting that this T-3 receptor variant may play a role in this hormonal responsiveness.