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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 (T4) 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 T4 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 T4 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 T3 but not T4 can suppress thyrotropin subunit beta 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.
Fig. 1. (A) Sibling tadpoles grown in 1 mM methimazole for several weeks.
Control tadpole (Right) at stage 53 treated for 8 days with 3 nMT3 (Center) and
3 nM T4 (Left). They were stained for cartilage with Alcian blue. (B) Tadpole
grown for 2 months in 1mMmethimazoley10 mMiopanoic acidy5 nMT4. In 1
month, the tadpole developed to stage 59 but then did not change further
during the final month of treatment.
Fig. 2. Developmental Northern blots with simultaneous hybridization with
D2 and D3 mRNAs. (A) Total tail RNA. (B) Hind-limb total RNA. (C) Pituitary
total RNA. This blot was hybridized only with the D2 probe. The numbers on
the tops of the lanes are tadpole stages.
Fig. 3. (A) Conversion of T4 to T3 in tadpolelimb buds but not tailtissue.
Stage-54 tadpoles were reared in methimazole with or without iopanoic acid
for 24 h and then incubated with [125I]T4 for 24 h followed by nonradioactive
medium for another 24 h. Limbs and tails were extracted in methanol for
radioactive TH, and the concentrated extracts were chromatographed. A lane
contains extract from four hind limbs or one tail. Hind limb (lane 1), tail (lane
2), and hind limb with iopanoic acid (lane 3). (B) Stage-59 tadpoles were
incubated in either iopanoic acid (IOP) or methimazole (MET) for 1 day and
then were incubated for a day in 0.5 mCiyml radioactive NaI. TH was extracted
from whole tadpoles and separated by TLC. Duplicate samples were chromatographed,
and each lane represents about one-third of a tadpole. CON,
control.
Fig. 4. Northern blot of various pituitary and hypothalamic hormones. Total
RNA was purified from pituitary and part of the brain (from midbrain to
cerebellum) of individual animals, and the entire sample was loaded in a lane.
The tadpoles treated with methimazole (MET) for several months were arrested
at stage 53, judging from the limb criteria. Two normal stage-53
tadpoles and 2 stage-66 froglets were used as controls. The same blot was
hybridized successively with the radioactive probes.
Fig. 5. In situ hybridization of sagittal sections of the pituitary (arrowhead) of stage-62 brains. (A) Hematoxylin and eosin stain. (B–J) In situ hybridization. (B)
D2 in situ in a section adjacent to A. (C) Higher magnification of D2 in the pituitary in B. (D) TSHb. (E) POMC. (F) Simultaneous in situ with POMC (orange) and
TSHb (purple). (G–J) Stage-58 tadpoles treated for 4 days with methimazole and iopanoic acid. (G and H) Simultaneous POMC and TSHb in situ, but both probes
were labeled with digoxigenin. (G) Stage-58 tadpoles treated for another 4 days with 10 nM T4. (H) Same as G, but treated for another 4 days with 10 nM T3.
(I) D2 in situ of doubly inhibited stage-58 tadpole. (J) Same as I except treated for 4 days with 10 nM T4. (Bar for A and B 5 200 mm.) (Bar for C–J 5 100 mm.) In
all figures, anterior is left and dorsal is up.
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