Integrative and Comparative Biology Advance Access originally published online on August 30, 2006
Integrative and Comparative Biology 2006 46(6):815-826; doi:10.1093/icb/icl035
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Evolution of the thyroid hormone, retinoic acid, ecdysone and liver X receptors
* Department of Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, USA
Department of Bioengineering, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093-0693, USA
Department of Medicine, University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093-0693, USA
Correspondence: 1E-mail: mbaker{at}ucsd.edu
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Ecdysone and thyroid hormone are 2 ligands that have important roles in regulating metamorphosis in animals. Ecdysone is a steroid that regulates molting in insects. Thyroid hormone regulates differentiation and development in fish and amphibia. Although ecdysone and thyroid hormone have different chemical structures, both hormones act by binding to transcription factors that belong to the nuclear receptor family. We investigated the evolution of structure and function in the ecdysone receptor (EcR) and thyroid hormone receptor (TR), and liver X receptor (LXR) and retinoic acid receptor (RAR), which cluster with EcR and TR, respectively (Bertrand S, Brunet FG, Escriva H, Parmentier G, Laudet V, Robinson-Rechavi M. 2004. Mol Biol Evol 21:1923–37), by constructing a multiple alignment of their sequences and calculating ancestral sequences for TR, RAR, EcR, and LXR. These alignments were mapped onto the 3D structures of TR, RAR, EcR, and LXR in the Protein Data Bank to examine the evolution of amino acids involved in the binding of ligands to TR, RAR, EcR, and LXR.
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Introduction |
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Metamorphosis is a process of dramatic developmental changes that mark a transition in the life cycle of an organism, allowing it to occupy a new habitat and consume different food sources. Here, we focus on 3 important signals for metamorphosis in animals: ecdysone, retinoic acid, and thyroid hormone (Fig. 1).
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Ecdysone triggers the activation of major developmental phases of metamorphosis in insects and crustaceans (Thummel 1996
; Gilbert and others 2002; Truman and Riddiford 2002; Bonneton and others 2003). For example, in Drosophila, during pupal development, transformation between each stage is activated by 20-hydroxyecdysone until the final adult emerges. A similar role for ecdysone has been found in a variety of other insect species. It has also been shown in more distant relatives of Drosophila that ecdysone has a role in development.
Thyroid hormone (T3) regulates metamorphosis in fish and amphibians (Power and others 2001; Youson and Sower 2001; Crespi and Denver 2005; Heyland and others 2005; Tata 2006). In Amphibia, T3 regulates the metamorphosis of tadpoles into frogs. After the tadpole emerges from the egg, the tadpole lives in the water, breathes with gills, and has a tail. As the tadpole grows under the influence of T3, the tadpole develops lungs and legs, and the gills and tail are absorbed into the body. After undergoing these changes, the frog leaves the water and lives mainly on land.
Retinoic acid is another important regulator of morphogenesis in deuterostomes (Gudas 1994; Mark and others 2006; Marletaz and others 2006).
Ecdysone, thyroid hormone, and retinoic acid act by binding to the ecdysone receptor (EcR), thyroid hormone receptor (TR), and retinoic acid receptor (RAR), respectively. These receptors are transcription factors that belong to the nuclear receptor family, which also includes receptors for various steroids (for example, aldosterone, estradiol, testosterone, cortisol, and progesterone), prostaglandins, vitamin D3, and oxysterols (Laudet 1997; Escriva and others 2000; Olefsky 2001; Thornton 2001; Baker 2002). This diverse family of transcription factors evolved through a series of gene duplications followed by divergence to recognize different ligands and regulatory sequences on DNA in the nucleus.
Due to the importance of TR, RAR, the estrogen receptor (ER), the glucocorticoid receptor (GR), and other nuclear receptors in many physiological pathways in animals, there has been extensive effort to sequence their genes in order to understand structure and function. Functional analysis of ligand-activated nuclear receptors reveals that hormones such as T3, retinoic acid, ecdysone, estradiol, and cortisol bind to a domain of 
250 amino acids at the C-terminus. In this paper we focus on the evolution of structure and function of the hormone binding domain in the EcR and TR, as well as liver X receptor (LXR) and RAR, which are close relatives of EcR and TR, respectively.
We already know much about the evolution of these and other nuclear receptors from previous phylogenetic analyses (Laudet and others 1992; Baker 1997; Laudet 1997). These analyses led to the organization of nuclear receptors into 6 subfamilies, from NR1 to NR6 (Laudet 1997). RAR clusters with TR in NR1A, and EcR clusters with LXR in NR1H. Interestingly, adrenal and sex steroid receptors cluster in NR3.
Further advances in understanding the origins of nuclear receptors have come from sequencing of various genomes from bacteria, yeast, animals, and plants. Searches of these genomes with probes for nuclear receptors revealed that bacteria, yeast, and plants do not contain nuclear receptors. Nuclear receptors are restricted to animals (Escriva and others 1997).
Genomic analysis also has been used to determine when different classes of nuclear receptors arose (Baker 2003; Bonneton and others 2003; Bertrand and others 2004). For example, BLAST searches revealed that there is no apparent ortholog of adrenal and sex steroid receptors in either Drosophila melanogaster or Caenorhabditis elegans. The soon-to-be-completed genomes for other protostomes, including mollusks, leeches, flatworms, jellyfish, and sponges will provide a more complete genomic database of organisms that arose at the base of the metazoans. It is hoped that these additional genomes will provide information that will answer questions such as: When did the common ancestor of the TR and RAR evolve? What was its original function? What ligand(s) activated the TR/RAR ancestor; that is, did the TR/RAR ancestor bind T3 or retinoic acid, or both, or a different ligand?
Until recently, this kind of analysis would be done by constructing a multiple alignment of sequences from phylogentically distant organisms in order to identify conserved residues that are likely to be important in hormone binding. Functional importance of conserved residues would be investigated further by mutagenesis studies.
The crystal structure of a receptor complexed with its hormone is a direct way to identify key residues in the hormone-binding site. Thus, the report of the crystal structure of RAR (Renaud and others 1995) was a major advance in deciphering the key residues involved in binding retinoic acid. As a result it became possible to investigate the evolution of retinoic acid-binding domain on RAR using its 3D structure along with multiple sequence alignment of RAR in phylogenetically diverse organisms.
Soon after the report of the 3D structure of the RAR, other nuclear receptors were crystallized with their hormones. From these structures, it became clear that nuclear receptors contained some common motifs in their hormone-binding domains (Fagart and others 1998; Egea and others 2000). Although this yielded a greater understanding of the structure of TR, EcR, and LXR, one still needs their crystal structures in order to confidently analyze their hormone-binding domains. In the past 3 years, these 3D structures have been solved with ligands (Billas and others 2003; Williams and others 2003; Sandler and others 2004; Carmichael and others 2005). As a result, we now know much about how each receptor interacts with ligands. However, a comparative analysis of EcR and LXR or RAR and TR has not been done. Such an analysis, when combined with recently reported sequences from basal deuterostomes can further elucidate the evolution of their hormone-binding domains. Here, we report the use of this strategy to study the evolution of amino acids involved in hormone binding of TR and RAR as they diverged from the ancestral TR/RAR. We also trace the evolution of LXR from EcR.
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Sequence collection
The sequences of TR, RAR, and LXR were collected from GenBank using human receptors as a BLAST query (Altschul and others 1990
). EcR sequences were collected using the D. melanogaster sequence as a BLAST query. A multiple alignment of these sequences was created using ClustalX (Thompson and others 1997). ClustalX was also used to create phylogenetic trees with the neighbor-joining method (Saitou and Nei 1987).
Construction of ancestral sequences
The ClustalX alignment of the hormone-binding domains was inputted into an ancestral protein algorithm, ANCESCON (Cai and others 2004), to determine the ancestral sequences of TR, EcR, LXR, and RAR. Several ancestral hormone-binding domains were calculated, including ancestral vertebrate TR, insect EcR, and arthropod EcR. For example, to determine the ancestral vertebrate TR, the TR sequences were extracted from GenBank and then ancestors were calculated for land animal TR
and TRß, and fish TR and TRß. These ancestors and 2 lamprey TRs (denoted TR1 and TR2) were used to construct the ancestral vertebrate TR.
Structural analysis
We used the 3D structures of TR (1XZX), EcR (1R1K), RAR (2LBD), and LXR (1P8D) from the Protein Data Bank (Berman and others 2000) to identify amino acids in each receptor that are in contact with bound hormone.
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Sequence and phylogenetic analysis
The ClustalX alignment of selected sequences of TR, RAR, EcR, and LXR is shown in Supplement Figures 1 and 2. Phylogenetic trees of selected hormone-binding domains for TR, RAR, EcR, and LXR, including calculated ancestors, are shown in Figure 2. The branching of the 4 different nuclear receptors is in agreement with previous phylogenetic analyses (Laudet 1997
; Bonneton and others 2003; Bertrand and others 2004; Baker 2005).
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Structural analysis of the hormone-binding domain
The amino acids on human TRß, human RAR
, moth EcR, and human LXRß that are in contact with bound hormone have been previously described (Renaud and others 1995; Billas and others 2003; Williams and others 2003; Sandler and others 2004). Figures 3 and 4 show the amino acids in human TRß and moth EcR that interact with T3 and ponasterone A (ponA), respectively. The amino acids on human RAR and human LXRß that interact with retinoic acid and oxysterol, respectively, are shown in Figures 5 and 6. We mapped the amino acids on human TR that interact with T3 onto the sequences from other TR orthologs to investigate the conservation of key residues in TR. In addition, we mapped these residues onto its RAR relative. A similar analysis was performed for EcR with other arthropod EcRs and for human LXR with its orthologs. These data are summarized in Tables 1–4.
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Hormone binding of TR
and TRßWagner and colleagues (2001)
determined the amino acid residues that interact with the iodine groups of T3. Residues of TR that interact with T3 are shown in Figure 3. These include His-435, which interacts with the hydroxyl group of the outer ring, as well as Arg-282 and Arg-320, which interact with the carboxylate group at the other end of the hormone.
Wagner and colleagues (2001) also showed that the functional difference between hormone-binding pockets of TR and TRß resides in the difference between Ser-277 in TR and Asn-331 in TRß. This change alters the conformation of the hormone-binding pocket in the 2 TR receptors. In TR complexed with Triac (3,5,3'-triiodothyroacetic acid), a T3 analog, Arg-228 rotates towards Triac and forms a hydrogen bond to Ser-277. In TRß, the corresponding arginine rotates away from the ligand. This difference does not change the binding affinity for T3 or Triac, but it does cause a variation between TR and TRß in affinity for ligands such as GC-1, which binds 3-fold tighter to TRß (Wagner and others 2001).
While TR and TRß differ in their ability to bind certain compounds, they both bind T3 with high affinity and T4 with 30-fold lower affinity. T4 is nearly identical to T3, but with a 5'-iodine group on the outer ring. Sandler and colleagues (2004) showed that compared to TR complexed with T3, the hormone-binding pocket in TR complexed with T4 is expanded, causing shifts in the side chains that result in steric clashes between 5'-iodo and the side chains of Met-310, Phe-455, and Phe-459. As shown in Supplement Figure 1, human Met-310 is conserved in all available TRs and with the exception of Ciona TR, Phe-455 and Phe-459 are conserved in other TRs.
Hormone binding of EcR
Billas and colleagues (2003) solved the crystal structure of moth EcR in complex with ponA, an ecdysteroid nearly identical to 20-hydroxyecdysone, but lacking the 25-hydroxyl group. Selected amino acid residues that interact with ponA are shown in Figure 4. Several polar residues interact with the hydroxyl groups of ponA: Thr-343, Thr-346, Arg-383, and Tyr-408. Billas and colleagues (2003) demonstrated the flexibility of hormone binding in EcR by solving the structure of EcR in complex with a non-steroidal bisacylhydrazine agonist and observing that the hormone binding cavity adopted a significant different conformation than when bound with ponA.
RAR and retinoic acid
The interaction between human RAR and all-trans retinoic acid is shown in Figure 5. Eleven residues surround and stabilize the isoprene tail and ß-ionone ring of retinoic acid through hydrophobic interactions; and 3 hydrophilic residues, Arg-278, Ser-298, and Lys-236 interact with the carboxylate group of retinoic acid (Renaud and others 1995). In Supplement Figure 3, we show selected hormone-binding residues of RAR overlapped with corresponding residues in TR.
LXR and epoxycholesterol
Human LXRß bound with eCH [24(S),25-epoxycholesterol] is shown in Figure 6. Sixteen residues comprise the LXRß binding pocket, which completely surrounds the hormone in a way similar to the other receptors. Hydrophilic interactions include His-435, which hydrogen bonds with the epoxide oxygen, and Asn-239, Glu-281, and Arg-319, which interact with the A-ring hydroxyl group (Williams and others 2003). Supplement Figure 4 shows selected hormone-binding residues of LXRß superimposed on corresponding residues in EcR.
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Discussion |
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The continued expansion of the database of sequences of TR, EcR, RAR, and LXR and the availability of their 3D structures has allowed us to investigate the evolution of the hormone-binding domains on these receptors. Our analysis provides insights into the similarities and differences in the evolution of key structural amino acids in TR and RAR, as well as EcR and LXR, as discussed below.
TR is highly conserved in vertebrates
The hormone-binding domain of TR shows significant conservation throughout all fish and animal sequences. This conservation leads to an ANCESCON reconstructed vertebrate TR ancestor that is 84% identical to human TR and 82% identical to human TRß. This bias towards TR results from both lamprey TR sequences being closer to TR than to TRß. Lamprey TR1, for example, is 79% identical to human TR and 75% identical to human TRß. This suggests that TR might be more conserved than TRß from the true ancestral vertebrate TR.
The lamprey TR sequences have asparagine-331, which is the signature of TRß hormone specificity. The amino acid corresponding to this asparagine is serine in all TR except flounder and halibut, which both have an asparagine in this position. The reconstructed TR ancestor also has this asparagine, indicating that the ancestral vertebrate TR has TRß hormone specificity despite being closer in overall sequence to TR.
Sea urchin TR is closer to vertebrate TR than is Ciona TR
Interestingly, sea urchin TR is closer in sequence identity to vertebrate TR than is Ciona TR. Table 5 shows the similarity between the sequences of vertebrate TR and invertebrate TR. Sea urchin TR is 46% identical to the reconstructed vertebrate TR ancestor, whereas Ciona intestinalis TR is only 32% identical.
This relationship also exists for the hormone-binding residues of sea urchin TR and Ciona TR, as shown in Tables 1 and 2. Because the complete sequence of sea urchin TR has not been determined, we only have sequence for 14 of its 20 hormone-binding residues. Eight of these 14 residues are identical to the aligned vertebrate TR. Direct binding of either T3 or T4 to sea urchin TR has not been studied. Interestingly, echinoderms respond to thyroxine (Heyland and others 2004; Heyland and Moroz 2005).
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In contrast, Ciona TR, which does not bind T3 (Carosa and others 1998
), only contains 3 of these 14 residues are identical to the aligned vertebrate TR. Ciona TR lacks crucial hormone-binding residues found in both sea urchin and vertebrate TR. In Ciona TR, His-435 is replaced by phenylalanine, preventing it from forming a hydrogen bond to the 4'-hydroxyl of T3. There also is a phenylalanine in place of Ser-277 TR/Asn-331 TRß, a residue that affects the position of Arg-282 through hydrogen bonding. A large hydrophobic side chain in this position would likely disrupt the network of hydrogen bonds. These key differences can explain why C. intestinalis TR does not bind T3 with high affinity (Corosa and others 1998). Lack of binding of T3 by Ciona TR may explain the change in its sequence as due to loss of constraints to bind T3. Lack of T3 binding by Ciona TR is intriguing because T3 is an active hormone in Ciona. Three possible explanations for such T3 activity are the presence in Ciona of an undiscovered T3 receptor, action of T3 through a membrane receptor or activation of Ciona TR by a metabolite of T3.
RAR is highly conserved in vertebrates
The differences among vertebrate RARs are not as large as the differences among vertebrate TRs. Table 6 shows the similarity between the sequences of human RAR,ß, with various RARs. Ciona RAR is 58% identical to human RAR, whereas Ciona TR is only 36% identical to human TR. Lamprey RAR is closer in sequence to human RAR than lamprey TR is to human TR. Sea urchin RAR, however, is less similar to human RAR than sea urchin TR is to human TR.
As shown in Tables 1 and 2, with the exception of sea urchin RAR, there is greater conservation of the hormone-binding residues of RAR in deuterostomes than there is in TR. Of the 14 RAR hormone-binding residues, 12 are conserved in Ciona and 9 are conserved in amphioxus. The 3 residues that interact with the carboxylate of retinoic acid (Arg-278, Ser-289, and Lys-236) are conserved in Ciona RAR and Polyandrocarpa RAR. Key differences occur in Lys-236 and Ser-289, which are glutamate and isoleucine in amphioxus and arginine and threonine in sea urchins.
Retinoid binding to sea urchin RAR has not been studied. Our analysis suggests that sea urchin RAR may respond to novel ligands.
Comparison of 3D structures of hormone-binding pockets in TR and RAR
In our analyses in Supplement Figure 1 we used a multiple sequence alignment to investigate conservation in orthologs of amino acids that bind T3 in TR and retinoic acid in RAR. We also investigated the conservation of hormone-binding residues in both TR and RAR by comparing their 3D structures complexed with T3 and retinoic acid. Interestingly, some hormone-binding residues of TR and RAR are conserved despite structural differences between T3 and retinoic acid.
The hormone-binding residues in both human TRß and human RAR are shown superimposed in Supplement Figure 3. Three of these residues, Arg-316/Arg-274 (TR/RAR), Arg-320/Arg-278, and Thr-329/Thr-287 are located near the carboxylate group of the hormone. Arg-320/Arg-278 is also conserved in other nuclear receptors, such as the mineralocorticoid receptor, GR, and ER (Fagart and others 1998), which belong to the NR3 subfamilies of nuclear receptors. Arg-278 in RAR interacts directly with the carboxylate of retinoic acid, while Arg-320 in TR is turned away and forms a water-mediated hydrogen bond to the carboxylate of T3.
Another conserved residue, Phe-272/Phe-230, is located near the middle of the hormone. In RAR, the C
atom of Phe-230 is oriented toward retinoic acid; in TR, Phe-272 is rotated 90° to make room for both the 3'-iodo and 3-iodo groups of T3.
A key difference between the TR and RAR hormone-binding pockets is His-435 in TR, which is a glycine in RAR. Since retinoic acid does not have a hydroxyl group on its ß-ionone ring, retinoic acid would not interact with a large hydrophilic side chain at this position in RAR. Another difference is Arg-282 in TR, which is lysine in RAR. Although arginine and lysine are considered to be conservative replacements of each other, their functions are different in TR and RAR. In TR, Arg-282 hydrogen bonds to the carboxylate group of T3, while the corresponding lysine in RAR does not interact with the carboxylate group of retinoic acid. Instead, lysine is oriented away from the ligand, forming a hydrogen bond with a glutamate.
TR and RAR are more conserved than are steroid hormone receptors
The high conservation of TR and RAR hormone-binding domains is not found in adrenal and sex steroid receptors. Tables 5 and 6 shows that human RAR is 85% identical to lamprey RAR and human TR is 75% identical to lamprey TR. As shown in Table 7, the progesterone receptor and ER are only 62 and 58% identical to their lamprey homologs, respectively.
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Hormone selectivity of ancestral EcR
The alignment of EcR hormone-binding domains in Supplement Figure 2 shows that the hormone-binding residues of EcR are less conserved across species than are the hormone-binding residues of vertebrate TR or RAR. Carmichael and colleagues (2005)
previously examined these residues and provided insights into the hormone selectivity of EcR from different orders of insects, allowing us to identify the potential hormone selectivity of our calculated EcR ancestors. The hormone-binding residues of our calculated insect EcR ancestor match the consensus for hemipteran and dipteran insects, indicating possible hemipteran and dipteran hormone selectivity. Our calculated arthropod EcR ancestor differs from the insect sequences with an alanine in place of Val-384. This replacement is also seen in ticks, suggesting tick-like hormone selectivity in the ancestral EcR.
Comparison of 3D structures of hormone-binding pockets in EcR and LXR
As we found for TR and RAR, comparison of the 3D structure of the hormone-binding domains of EcR and LXR revealed that some hormone-binding residues are conserved (Supplement Figure 3). Specifically, Phe-397/Phe-329 (EcR/LXR) and Met-380/Met-312 have hydrophobic interactions with the center of the hormone, and Arg-387/Arg-319 interacts with the C3-OH group of both ponA and eCH. Trp-526/Trp-457 has been proposed to be part of a tryptophan/histidine activation switch in LXR (Williams and others 2003). Carmichael and colleagues (2005), however, suggested that this tryptophan does not participate in an activation switch in EcR because this would not explain why ponA, which lacks the 25-hydroxyl group, is an agonist for EcR.
Several amino acids of EcR that interact with the hydroxyl groups of ponA are not conserved in LXR, which likely is due to the absence of these hydroxyl groups in the ligands that bind LXR. For example, Tyr-408 in EcR, which forms a strong hydrogen bond to the 20-OH group of ponA, is a phenylalanine in LXR. Other key differences between the hormone binding pockets of EcR and LXR include Arg-383/Glu-281 and Glu-309/Asn-239.
Similarities between EcR and sea urchin LXR
It is interesting to note that the differences between EcR and Ciona or sea urchin LXR are not as large as the differences between EcR and human LXR (Tables 2, 4, 8 and 9). For example, 9 of the 20 hormone-binding residues of EcR are conserved in sea urchin LXR, whereas only 4 are conserved in human LXR. Among these conservations specific to sea urchin LXR are Thr-343, Thr-346, and Arg-383. In EcR, these residues interact with hydroxyl groups of ponA that oxysterols such as eCH lack. Ligand binding to sea urchin LXR has not been studied. Our analysis suggests that sea urchin LXR can recognize different ligands than does human LXR. Indeed, sea urchin LXR may even bind a hormone that resembles an ecdysteroid.
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We have analyzed the evolution of hormone-binding in TR, RAR, EcR, and LXR by using information from an alignment of the sequences of their orthologs in animals and 3D structures of these receptors co-crystallized with hormones. Our analysis can explain the lack of binding of T3 to Ciona TR. It also predicts that sea urchin LXR is a close descendent of the EcR. This comparative analysis of 3D structures and sequences from phylogenetically distant organisms has much promise for application towards understanding the evolution of other nuclear receptors and enzymes that regulate hormone concentrations. Our analysis further emphasizes the need for complete sequencing of additional genomes from animals at the base of the deuterostome line and in protostomes. With this information, it should be possible to continue to improve our understanding of the origins TR/RAR and EcR/LXR and their subsequent diversification in metazoans.
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Acknowledgements |
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We would like to thank all audience-members from the platform and associated-sessions for constructive discussions. We are grateful to the Society for Integrative and Comparative Biology (SICB) for promoting and partially funding this symposium. Furthermore, we would like to thank the following organization for their generous financial support: the University of Florida, The Whitney Laboratory for Marine Biosciences, the American Microscopical Society (AMS), and the SICB Division of Evolutionary Developmental Biology (DEDB).
Conflict of interest: None declared.
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Footnotes |
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From the symposium "Metamorphosis: A Multikingdom Approach" presented at the annual meeting of the Society for Integrative and Comparative Biology, January 4–8, 2006, at Orlando, Florida.
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