Here, we examine the possible requirement of GC signaling and interaction with TH for metamorphosis. The best known role of GCs in metamorphosis is to synergize with TH to accelerate TH-induced metamorphosis in Xenopus 14 , 17 and in axolotl On the other hand, exogenous CORT by itself does not induce metamorphic development, and in fact inhibits growth and development in premetamorphic tadpoles , Surprisingly, even when administered during prometamorphosis when endogenous TH is present, exogenous CORT still inhibits metamorphosis in Xenopus laevis but accelerates development by itself in toad species , Inhibitory effects of exogenous GCs administered during prometamorphosis may be acting at the level of the hypothalamus resulting in lower plasma TH, but this possibility has not been tested.
Also, even though TH-response gene induction may not be required for metamorphosis see above discussion , it is likely that CORT is required for survival through metamorphosis.
In particular, only TH plus ACTH adrenocorticotropic hormone, the pituitary hormone that stimulates production of GCs , but not TH alone, enabled survival through metamorphosis of hypophysectomized tadpoles In contrast, lack of metamorphosis in hypothalectomized hypothalamus removed, blocks stimulation of pituitary hormones required for TH and GC production could not be rescued by treatment with TH and ACTH It is possible that the explanation for GC acceleration of TH-induced metamorphosis, death from lack of GC signaling, and the observed discrepancies between natural and induced metamorphosis may be related to TH tissue sensitivity.
The increased tissue sensitivity induced by GCs see below can explain acceleration of TH-induced metamorphosis by GCs, where increased TH sensitivity would increase TH signaling and thus the rate of metamorphic development. Also, death from lack GC signaling and failure of exogenous TH to completely replicate natural development, which presumably includes a lack of a surge in GCs, may be due to lack of GC-induced increase in TH sensitivity, such that insufficient TH sensitivity may disallow development of a critical organ system before TH levels return to baseline or may lead to disruptions of the normal series of asynchronous developmental events e.
On the other hand, high exogenous TH doses would presumably negate a need for GC-dependent increases in TH sensitivity.
Thus, distinct from altered TH sensitivity, direct and required actions of GCs may explain death from lack of GC signaling and may also explain discrepancies between natural and induced metamorphosis.
These modes of GC interaction with TH-dependent development, namely altered TH tissue sensitivity and direct effects of GCs, are discussed in the following sections. Deiodinases are a family of enzymes that catalyze the release of iodine from TH leading to the production of T3 the most active form of TH from T4 often considered a prohormone and binds with lower affinity to TH receptors and to the degradation of T4 and T3 Several studies have shown that the acceleration of TH-induced metamorphosis by GCs is partly due to the increased availability of TH in cells through GC effects on deiodinase expression or activity.
First, GCs increased D2 activity in tadpole tissues associated with increased generation of T3 from T4 in Lithobates catesbeianus 16 and Anaxyrus boreas Overall, these two actions of GCs contribute to the global increase in TH availability in metamorphosing tissues.
Similarly in the neotenic amphibian, the axolotl Ambystoma mexicanum , treatment with dexamethasone a synthetic glucocorticoid increased D2 activity and decreased D3 activity, and such changes were accompanied by an increase in plasma T3 levels The level of TR gene expression is another central component of TH sensitivity TH acts by binding to TR that functions as a ligand-activated transcription factor.
The number of functional TRs expressed by a cell in large part determines the cell's sensitivity and responsivity to T3 , TH itself can induce the expression of TR autoregulation in tadpoles, thus increasing the sensitivity to TH and driving the transformation process In addition to autoregulation, other stimuli can influence the expression of TR cross-regulation Such cross-regulation by GCs was first shown in bullfrog tadpole tail fins, where an increase in nuclear binding capacity for T3 was observed In contrast, T3 treatment or spontaneous metamorphosis lead to an increase in the number of T3 binding sites per nucleus in Lithobates catesbeianus red blood cells, but surprisingly this effect was abolished by dexamethasone glucocorticoid receptor agonist and sustained by dexamethasone plus RU glucocorticoid receptor antagonist TRs directly regulate numerous genes, some of which are transcription factors that in turn regulate the expression of other genes in a gene regulation cascade Several members of this family were shown to be effectors of nuclear receptor signaling.
Specifically, the KLFs can act as accessory factors for nuclear receptor actions, can regulate expression of nuclear receptor coding genes, and can be regulated directly by nuclear receptors. Klf9 in particular is directly induced by GCs in a protein synthesis independent fashion exclusively via GR in tail, lungs, and brain 58 , It was further observed that GCs synergize with TH to superinduce the expression of klf9 This direct TH and GC regulation of klf9 is evolutionary conserved as it also occurs in mammals To explain how both TH and GCs synergize to increase klf9 mRNA expression, a highly conserved bp genomic region of the Xenopus and mouse klf9 genes was identified 5—6 kb upstream of the transcription start site with binding sites for TR and GC receptor GR , Characterization of this region has shown that TH increased the recruitment of liganded GR to chromatin at the enhancer element and that chromosomal looping allows the interaction of this far upstream enhancer region 5—6 kb with the klf9 promoter.
This transcriptional mechanism of GC and TH interaction is known for just this gene, klf9 , but there are likely other synergistic genes when considering that GCs synergize with TH to increase the rate of numerous morphological changes occurring during metamorphosis. Thus, Klf9 acts as an accessory transcription factor with TRs at TR direct target genes, which increases cellular responsivity to further TH action on developmental gene regulation programs TH affects GC signaling in at least two ways.
First, T4-treatment, but not T3, increased whole body-GC levels in Anaxyrus boreas tadpoles, and a corticoid synthesis inhibitor prevented the stimulatory effect of T4 on GC production Second, TH may regulate GR expression, at least in some tissues. During natural metamorphosis with its rising plasma TH titers, GR mRNA increases in the brain, lungs, and tail, but not intestine 58 , However, T3 treatment increased GR expression in the tail and decreased it in the brain intestine and lungs were not assessed 14 , Mineralocorticoid receptor MR, the other nuclear receptor for GCs increased during natural metamorphosis in brain, lungs, and tail and was shown to be inducible in the tail 58 , Thus, the synergy of T3 with GC during metamorphosis involves tissue-specific and T3-dependent regulation of GR transcripts.
As shown above, exogenous TH does not always replicate natural metamorphosis. It is easy to add saturating amounts of TH to rule out insufficient TH signaling as the reason for the discrepancy in induced vs. Also, the lack of metamorphic completion associated with lack of GC signaling suggests that TH is not sufficient and that direct action of GCs not related to TH signaling is required.
An important issue, then, is to distinguish between TH and GCs working simultaneously on the same cell vs. Also, at the level of gene expression, some changes in gene regulation in the presence of both TH and GCs are inconsistent with the synergistic morphological actions of the two hormones together.
High throughput technologies provide a global perspective to help understand the mechanisms of interaction between TH and GCs. Previously, only one GC response gene was known in tadpoles, i. Microarray analysis identified over 5, genes whose expression was significantly modified in response to one or more hormone treatments and offered a new opportunity to dissect the interaction between TH and GCs.
Cluster analysis led to the identification of numerous patterns of gene regulation Figure 2. These antagonistic hormone interactions at the gene expression level contrast sharply with the solely synergistic action of these hormones at the morphological level, i. The unexpectedly complex and uncharacterized mechanisms of gene regulation for a large number of genes controlled by TH and GCs represents an open frontier in need of future research to understand how developing organisms interact with the environment to modulate development via altered hormonal input.
Figure 2. Shown are idealized patterns of changes in gene expression induced by hormone treatments relative to control levels based k-means clustering of significantly regulated genes among treatments To expand the understanding of the hormonal cross talk and link clustering with biological functions, gene ontology GO analysis was applied to the gene lists The genes significantly regulated by T3 Figure 2 , TH-only genes included GO categories, corresponding to programmed cell death and metallopeptidase activity.
It makes sense that an increase in T3 would increase the expression of genes involved in tissue resorption. Again, it makes sense that an increase in GCs increases the expression of genes involved in gluconeogenesis to regulate energy requirements for altered metabolism during stress and provide sufficient energy for the acceleration of metamorphosis.
Genes synergistically up-regulated when CORT and T3 were present together Figure 2 , synergistic induced genes include GO terms associated with intracellular protein transport, vesicle-mediated transport, protein localization, and cellular localization.
Finally, genes that are down-regulated by T3 and CORT co-treatment Figure 2 , synergistic repressed genes are linked with negative regulation of development and cell differentiation. Globally, these results are consistent with the action of the two hormones to promote tail resorption. It is important to note, however, that the proportion of genes that emerge from GO analysis is small relative to the number of differentially expressed genes.
Thus, the ontology analysis results do not reflect all the functions represented by the differentially expressed genes. There remains, therefore, an important part of the data for which we are not yet in a position to define the biological function. The number of patterns of TH- and GC-response gene regulation Figure 2 suggests that multiple molecular mechanisms likely exist to provide this gene regulation diversity.
Research into these mechanisms of interest benefits from knowledge that T3 and GCs act directly through nuclear receptors that initiate gene regulation cascades of induced transcription factors 20 , Identifying direct response genes for each hormone is a key element of on-going research.
TH and GCs regulate gene expression via hormone response elements HRE that interact with the promoter of hormone direct target genes 23 , The identification of such HREs is difficult because of the complexity of these elements First, HRE sequences may be partially degenerate, engendering numerous false positives identified by sequence analysis algorithms. Second, the presence of an HRE sequence does not guarantee the binding of the receptor, presumably because the chromatin organization around an HRE can dictate the accessibility of the HRE to receptors.
Finally, the HRE position relative to the promoter of the target gene can be near or far upstream or downstream of the gene and also within the gene Despite advances in knowledge and computer algorithms, currently only experimentation can allow the identification of HREs Such information is still not available for GC-response genes, except for klf9.
Note that all known HREs are positive, resulting in up-regulation of the gene in response to the hormone. HREs can be either positive or negative, but the existence of negative HREs remains to be established. However, antagonistic interactions may be indirect due to induced transcription factors or chromatin modifiers affecting hormone response gene expression. Indeed, sox3, dot1L , and de novo DNA methyltransferase 3 are direct T3 response genes that themselves affect chromatin structure and gene expression — Numerous explorations into the hormonal control of frog metamorphosis have revealed the powerful effects of TH on nearly every tissue in the tadpole body.
These studies have also identified limitations in our ability to replicate these developmental events using exogenous TH. These limitations may be artifacts of the experimental hormone treatments, or TH may indeed be insufficient to accomplish all of the developmental changes of metamorphosis. The relative ease of eliminating TH to study its role in development is contrasted with the difficulty of selectively removing other hormones, as yet unachieved for GCs, aldosterone, prolactin, that may also play a role in natural development.
The advent of gene disruption technologies to produce loss of function mutations in pituitary hormones, steroid synthesizing enzymes, and hormone receptors opens the door for continued advances to understand the roles of other hormones besides TH involved in the complex endocrine mechanisms that control post-embryonic development in amphibians.
LS and DB have conceived the presented idea and contributed to the writing of the paper. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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