Further Development 21.2: From Pre-Metamorphosis to Metamorphic Climax

Metamorphosis: The Hormonal Reactivation of Development

Metamorphosis is often divided into stages based on the concentration of thyroid hormones in the blood. During the first stage, pre-metamorphosis, the thyroid gland has begun to mature and is secreting low levels of T4 and very low levels of T3. The TRα receptor is present but the TRβ receptor is not. T4 secretion may be initiated by corticotropin-releasing hormone (CRH, which can be activated either developmentally or by external stresses). CRH generates steroids such as corticosterone. Corticosterone probably has two modes of action (Kulkarni and Bucholz 2014). First, it acts directly on the frog pituitary, instructing it to release thyroid-stimulating hormone (TSH), thereby initiating thyroid hormone synthesis. Second, it may act at the level of the promoter and enhancer of the hormone-responsive genes to make the responding cells more responsive to low amounts of T3 (Denver 1993, 2003).

The tissues that respond earliest to the thyroid hormones are those that express high levels of deiodinase II and thus can convert T4 directly into T3 (Cai and Brown 2004). For instance, the limb rudiments, which have high levels of both deiodinase II and TRα, can convert T4 into T3 and use it immediately through the TRα receptor. Thus, during the early stage of metamorphosis, the limb rudiments are able to receive thyroid hormone and use it to initiate leg growth (Becker et al. 1997; Huang et al. 2001; Schreiber et al. 2001).

As the thyroid matures to the stage of prometamorphosis, it secretes more hormones. However, many major changes (such as tail resorption, gill resorption, and intestinal remodeling) must wait until the metamorphic climax stage. At that time, the concentration of T4 rises dramatically and TRβ levels peak inside the cells. Since one of the targets of T3 is the TRβ gene, it is thought that TRβ is the principal receptor mediating the metamorphic climax. In the tail, there is only a small amount of TRα during premetamorphosis, and deiodinase II is not detectable. However, during prometamorphosis, rising levels of thyroid hormones induce higher levels of TRβ. At metamorphic climax, deiodinase II is expressed and the tail begins to be resorbed. In this way, the tail undergoes absorption only after the legs are functional (otherwise, the poor amphibian would have no means of locomotion). The wisdom of the frog is simple: “Never get rid of your tail before your legs are working.”


Literature Cited

Becker, K. B., K. C. Stephens, J. C. Davey, M. J. Schneider and V. A. Galton. 1997. The type 2 and type 3 iodothyronine deiodinases play important roles in coordinating development in Rana catesbeiana tadpoles. Endocrinology 138: 2989–2997.
PubMed Link

Cai, L. and D. D. Brown. 2004. Expression of type II iodothyronine deiodinase marks the time that a tissue responds to thyroid hormone-induced metamorphosis in Xenopus laevisDev. Biol. 266: 87–95.
PubMed Link

Denver, R. 1993. Acceleration of anuran amphibian metamorphosis by corticotropin-releasing factor-like peptides. Gen. Comp. Endocrinol. 91: 38–51.
PubMed Link

Denver, R. 2003. The vertebrate neuroendocrine stress system and its role in orchestrating life history transitions. Society for Integrative and Comparative Biology, Annual Meeting.

Huang, H., L. Cai, B. F. Remo and D. D. Brown. 2001. Timing of metamorphosis and the onset of the negative feedback loop between the thyroid gland and the pituitary is controlled by type II iodothyronine deiodinase in Xenopus laevisProc. Natl. Acad. Sci. USA 98: 7348–7353.
PubMed Link

Kulkarni, S. S. and D. R. Buchholz. 2014. Coticosteroid signaling in frog metamorphosis. Gen. Comp. Endocr. 203: 225–231.
PubMed Link

Schreiber, A. M., B. Das, H. Huang, N. Marsh-Armstrong and D. D. Brown. 2001. Diverse developmental programs of Xenopus laevis metamorphosis are inhibited by a dominant negative thyroid hormone receptor. Proc. Natl. Acad. Sci. USA 98: 10739–10744.
PubMed Link


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