Two important features of amphibian metamorphosis are the sequential response of tissues to different concentrations of thyroid hormone (TH) and the development of the negative feedback loop between the pituitary and the thyroid gland that regulates TH synthesis by the thyroid gland. At the climax of metamorphosis in Xenopus laevis (when the TH level is highest), the ratio of the circulating precursor thyroxine (T 4) to the active form 3,5,3-triiodothyronine (T3) in the blood is many times higher than it is in tissues. This difference is because of the conversion of T 4 to T3 in target cells of the tadpole catalyzed by the enzyme type II iodothyronine deiodinase (D2) and the local effect (cell autonomy) of this activity. Limb buds and tails express D2 early and late in metamorphosis, respectively, correlating with the time that these organs undergo TH-induced change. T 3 is required to complete metamorphosis because the peak concentration of T 4 that is reached at metamorphic climax cannot induce the final morphological changes. At the climax of metamorphosis, D2 expression is activated specifically in the anterior pituitary cells that express the genes for thyroid-stimulating hormone but not in the cells that express proopiomelanocortin. Physiological concentrations of T 3 but not T4 can suppress thyrotropin subunit โค gene expression. The timing and the remarkable specificity of D2 expression in the thyrotrophs of the anterior pituitary coupled with the requirement for locally synthesized T3 strongly support a role for D2 in the onset of the negative feedback loop at the climax of metamorphosis. T he metamorphosis of anurans is controlled by a steadily increasing concentration of thyroid hormone (TH) in tadpoles. TH reaches a peak at the climax of metamorphosis and then falls as the final change, tail resorption, occurs (1, 2). This gradual increase in TH concentration is essential for the sequential development of frog tissues and organs (3, 4). The growth of the hind limbs is the earliest TH-induced morphological modification. In Xenopus laevis, the hind-limb buds form but cannot develop beyond Nieukoop Faber (NF) stage 53 (5) in the absence of TH. TH-induced growth and development of limbs occur when the endogenous TH concentration is low and is completed before the climax of metamorphosis (when TH concentration is the highest). Many metamorphic changes occur in rapid succession at climax. In about 4 days, the intestine remodels and the gills resorb followed by tail resorption, which takes another 3-4 days.A negative feedback loop between the thyroid gland, the pituitary, and the hypothalamus maintains the endogenous TH at a constant level in adults of higher vertebrates (6). The rising TH concentration in X. laevis tadpoles, which is so important for their sequential development, occurs paradoxically as the pituitary content of thyroid-stimulating hormone (TSH) mRNA is increasing also (7). Etkin (8) hypothesized that the rise in TH during the early part of tadpole development was caused by a positive feedba...