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Metamorphosis, classically defined as a spectacular post-embryonic transition, is well exemplified by the transformation of a tadpole into a frog. It implies the appearance of new body parts (such as the limbs), the resorption of larval features (such as the tail) and the remodelling of many organs (such as the skin or the intestine). In vertebrates, metamorphosis has been well characterized in anuran amphibians, where thyroid hormones orchestrate the intricate and seemingly contradictory changes observed at the cellular and tissue levels. Thyroid hormones control a complex hierarchical cascade of target genes via binding to specific receptors, TRα and TRβ, ligand-activated transcription factors belonging to the nuclear receptor superfamily. Metamorphosis is actually widespread in the vertebrates, though quite diverse in the way it manifests in a particular species. Furthermore, evolutionary and ecological variations of this key event, from paedomorphosis to direct development, provide an excellent illustration of how tinkering with a control pathway can lead to divergent life histories. The study of invertebrate chordates has also shed light on the origin of metamorphosis. The available data suggest that post-embryonic remodelling governed by thyroid hormones is an ancestral feature of chordates. According to this view, metamorphosis of the anurans is an extreme example of a widespread life history transition.
Figure 1.
Metamorphosis is widespread in the animal world.
(A) A simplified phylogenetic tree of chordates in relation to other animals, highlighting the chordate groups that are known to undergo metamorphosis and for which a link with thyroid hormones has been established (boxed in yellow). Note that all the other phyla of metazoans depicted in the tree contain many metamorphosing species. (B) Some larvae and adults of metamorphosing vertebrates. The numbers refers to the larvae panels, the Roman numerals to the adult panels. 1/i: The tadpole and an adult of the main model for studying vertebrate metamorphosis, the anuran Xenopus laevis. 2/ii: The tadpole and the adult of Ciona intestinalis, an urochordate. 3/iii: Larvae and adult of amphioxus; the larvae is asymmetric and the mouth, on the left side of the body, is not visible in the photo. 4/iv: Larvae and adult of lamprey; the larvae, also called the ammocete, is a P. marimus, the adult is a L. fluviatilis. 5/v: ambystomatids salamanders (the paedomorph A. mexicanum in 5, and A. californiense in v). 6/vi: Symetric larvae and asymetric adult of a flatfish, the sole (Solea sp.); 7/vii: An eight-day post-fertilization juvenile and an adult of zebrafish (D. rerio).
Figure 2.
Phylogeny of the thyroid hormone receptors.
At least four gene duplications (red circles) occurred during the evolution of the thyroid hormone receptor gene: one at the base of vertebrates, giving rise to TRα (NR1A1) and TRβ (NR1A2); one specific to teleost fishes, giving rise to TRα-A and TRα-B; an apparently independent duplication giving rise to two receptors in lamprey, called TR1 and TR2; and another apparently independent duplication in flatworms giving rise to two genes, tentatively called TRx and TRy. Two independent gene losses (red cross) occurred in insects and in nematodes. Note that protostome thyroid hormone receptors have not yet been shown to bind thyroid hormones: these genes are believed to encode thyroid hormone receptors purely on the basis of their orthology.
Figure 3.
The hypothalamo-pituitary-thyroid axis and the thyroid hormone signalling pathway.
From top to bottom: During Xenopus metamorphosis, the environment controls the production of CRF, which binds to specific receptors in the anterior pituitary and triggers the production of both TSH and ACTH. TSH acts on the thyroid gland to produce thyroid hormones, mainly T4 (80%) but also T3. ACTH controls the production of corticoids. All these hormones are transported in the blood via binding proteins and enter in the target cells via transporters. In the target cells thyroid hormones can be metabolized by deiodinases. Outer ring deiodinases (mainly deiodinase 2, D2) transform T4 into T3, which is responsible for the formation of the active hormone. In contrast, inner ring deiodinases (mainly D3) transform T4 and T3 into reverse T3 and T2, respectively, both being inactive compounds. In the nucleus, T3 binds to its receptor to form a heterodimer with RXR and activates specific target genes that contain thyroid hormone response elements (TREs) in their regulatory regions. Corticoids are also ligands for the glucocorticoid receptor (GR) another member of the nuclear receptor superfamily. This receptor is located in the cytoplasm without ligand and translocates into the nucleus after ligand binding. Here it binds DNA on specific response elements called GREs as a homodimer and activates target genes. Some cases of synergistic gene activation between TRâRXR and GR have been demonstrated. (Adapted with permission from [35].)
Figure 4.
Thyroid hormones and thyroid hormone receptors in flatfish metamorphosis.
(A) Comparison of the thyroid hormone titres and thyroid hormone receptor expression levels in Xenopus, the japanese flounder (Paralichthys olivaceus) and the Senegalese sole (Solea senegalensis). Given their economic importance for aquaculture, other species of flatfishes, such as the Atlantic halibut (Hippoglossus hippoglossus) and the turbot (Scophtalmus maximus), have been used as models to study the role played by thyroid hormones in post-embryonic development. Data from [3] (Xenopus), [42] (flounder), and [45] (sole). (B) Several steps of flounder metamorphosis illustrated, with in particular, by one eye that migrates to the opposite side of the head. (i) Early premetamorphosis at 12 days post-fertilization (dpf). (ii) Late pre-metamorphosis. (iii) Pro-metamorphosis with the onset of right eye migration; the fish swims with sustained 10â15° right tilt. (iv) Early metamorphic climax at 24 dpf; the right eye has migrated halfway to the dorsal mid-line. (v) Late metamorphic climax; the right eye is close to midline. (vi) Post-metamorphic juvenile at 30 dpf. (vii) Settled sub-adult; the right eye is on the left side of the head and adjacent to the left eye. (Reproduced with permission from [104].)
Figure 5.
Simplified phylogeny of ambystomatids salamanders.
The tree shows that several independent evolutions to paedomorphosis occurred in the group. Red, paedomorphic, never undergoing metamorphosis in the wild; orange, polymorphic, with both paedomorphic and metamorphosed individuals observed in the wild; blue, transforming, with all the population undergoing metamorphosis in the wild. The status of the branch was assessed by parsimony analysis and black lines indicate equivocal status. The pictures of the species are, from left to right: A. gracile, A. californiense, A. mexicanum, A. andersoni. (Tree reproduced with permission from [62].)
Figure 6.
Thyroid hormone regulated metamorphosis is an ancient feature.
(A) The model, shown on a phylogenetic tree of bilaterians, in which all chordates undergo a âmetamorphosisâ, defined as a post-embryonic remodelling period associated with high thyroid hormones and thyroid hormone receptor levels (see panel B). Note that the situation of some vertebrate groups (sauropsids, birds, cartilaginous fishes) remains largely unknown. Basal deuterostomes such as Echinoderms and Hemichordates are shown in a different shade to illustrate that there is still uncertainty for these phyla with respect to the precise role and mechanism of action of thyroid hormones. An intriguing possibility is that the common ancestor of all metazoans (Urbilateria) underwent metamorphosis controlled by thyroid hormones or thyroid hormone-like compounds. This would imply that Ecdysozoans evolved a distinct mode of metamorphosis, derived from moulting and controlled by ecdysteroids. (B) A sketch illustrating the importance of the intestine, an organ that is remodelled in most if not all cases of thyroid hormone-triggered âmetamorphosisâ is illustrated.
