In vivo expression of thyroid transcription factor-1 RNA and its relation to thyroid function and follicular heterogeneity: Identification of follicular thyroglobulin as a feedback suppressor of thyroid transcription factor-1 RNA levels and thyroglobulin synthesis

We used in situ hybridization to evaluate thyroid transcription factor-1 (T TF-1) RNA expression in individual follicles and related this to thyroglobu lin (Tg) synthesis in vivo, as estimated by immunohistochemical analysis. W e studied the thyroids of Wistar rats treated with thyroxine (T-4) Or propy lthiouracil (PTU), each of which modulates TSH levels, but affects follicul ar function and Tg accumulation in the follicular lumen very differently. W e show that TTF-1 RNA levels in vivo correlate directly with an increase in the cytoplasmic accumulation of Tg within the cells of individual follicle s. Because TTF-I increases Tg gene expression, RNA levels, and protein synt hesis in thyroid cell cultures and because there is no correlation with TSH -increased Tg degradation within the follicular lumen, the increased cytopl asmic accumulation of Tg in vivo is interpreted to reflect TTF-1-increased Tg synthesis. Increases in serum TSH levels in the PTU or T-4 treated anima ls did not always correlate with increases in this measure of increased Tg synthesis; and TSH levels did not always correlate with changes in TTF-1 RN A levels that would be expected to accompany increased Tg synthesis. As one possibility, this suggested there might be a hitherto unrecognized suppres sor of TTF-1 RNA levels and TSH-induced Tg synthesis in individual follicle s. The immunohistochemical data suggested that this suppressor might be fol licular Tg itself. Supporting this possibility, we show that physiological concentrations of highly purified 19S follicular Tg decrease TTF-1 RNA leve ls in rat FRTL-5 thyroid cells and inhibit the action of TSH to increase Tg synthesis. We therefore suggest that follicular Tg is a feedback autoregul ator of thyroid function that can counterregulate TSH actions on thyroid fu nction in vivo and in thyroid cells in culture. We suggest this phenomenon contributes to follicular heterogeneity in vivo.