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. Author manuscript; available in PMC: 2024 Jul 26.
Published in final edited form as: Vitam Horm. 2023 Mar 9;123:483–502. doi: 10.1016/bs.vh.2023.02.003

Steroid-receptor coactivator complexes in thyroid hormone-regulation of Xenopus metamorphosis

Yuta Tanizaki 1, Lingyu Bao 1, Yun-Bo Shi 1,*
PMCID: PMC11274430  NIHMSID: NIHMS2011343  PMID: 37717995

Abstract

Anuran metamorphosis is perhaps the most drastic developmental change regulated by thyroid hormone (T3) in vertebrate. It mimics the postembryonic development in mammals when many organs/tissues mature into adult forms and plasma T3 level peaks. T3 functions by regulating target gene transcription through T3 receptors (TRs), which can recruit corepressor or coactivator complexes to target genes in the absence or presence of T3, respectively. By using molecular and genetic approaches, we and others have investigated the role of corepressor or coactivator complexes in TR function during the development of two highly related anuran species, the pseudo-tetraploid Xenopus laevis and diploid Xenopus tropicalis. Here we will review some of these studies that demonstrate a critical role of coactivator complexes, particularly those containing steroid receptor coactivator (SRC) 3, in regulating metamorphic rate and ensuring the completion of metamorphosis.

1. Introduction

Ever since the discovery that one or more compounds in the thyroid could accelerate anuran metamorphosis over a century ago (Gudernatsch, 1912), anuran metamorphosis has been used as a model for studying postembryonic development in vertebrates, particularly the role of thyroid hormone (T3) during metamorphosis, and developmental regulation of organ regeneration (Dodd & Dodd, 1976; Gilbert & Frieden, 1981; Gilbert, Tata, & Atkinson, 1996; Li, Zhang, & Amaya, 2016; Marshall et al., 2019; Shi, 1999, 2013a; Tata, 1993; Wang & Shi, 2021; Yakushiji, Yokoyama, & Tamura, 2009). Metamorphosis in anurans, such as the highly related diploid Xenopus tropicalis and pseudo-tetraploid Xenopus laevis, resembles postembryonic development in mammals, a period around birth when plasma T3 level peaks and many organs/tissues mature into their adult form (Fig. 1A) (Shi, 1999; Tata, 1993). While it is difficult to study mammalian postembryonic development due to maternal influence, it is much easier to manipulate anuran metamorphosis. T3 plays a causative role in this process and its level can be easily altered by adding exogenous T3 or T3 synthesis inhibitors to tadpole rearing water to affect metamorphosis. In addition, T3 can even induce organ-specific metamorphic changes when added to organ cultures of premetamorphic tadpoles, indicating that individual tissues/organs are genetically programmed for specific T3-dependent changes. Furthermore, essentially all tissues/organs in an anuran tadpole are transformed during metamorphosis, involving drastic changes ranging from de novo formation of adult tissues such as the limb, remodeling of organs present in both tadpoles and frogs to adapt for post-metamorphic living habitat, to complete resorption of larval specific organs such as the tail (Fig. 1B). This makes it possible to use anuran metamorphosis to study diverse cellular processes during vertebrate development. The advantage of the anuran model is further strengthened by transgenic and gene-editing tools for genetic studies (Blitz, Biesinger, Xie, & Cho, 2013; Fu, Buchholz, & Shi, 2002; Kroll & Amaya, 1996; Lei et al., 2012; Lei, Guo, Deng, Chen, & Zhao, 2013; Nakade et al., 2014; Nakayama et al., 2013; Shi et al., 2015; Wang et al., 2015; Young et al., 2011), which had been a weakness for amphibian and fish models compared to the mouse model for vertebrate studies.

Fig. 1.

Fig. 1

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T3 and postembryonic development. (A) Plasma T3 levels peak during postembryonic development in human and anuran metamorphosis. Postembryonic development in mammals refers to the perinatal period when many organs mature into their adult forms, i.e., about 4 months before to several months after birth in human (Tata, 1993). This period corresponds to metamorphosis in anurans such as Xenopus laevis (Leloup & Buscaglia, 1977; Nieuwkoop & Faber, 1965). (B) Xenopus metamorphosis involves three major types of transformations: de novo development of adult organs such as limbs, complete degeneration of larval organs such as the tail, and remodeling of organs that are present in both tadpoles and frogs such as the intestine. Note that at least some T3-induced apoptosis occurs in these examples of all three types. EP, epithelium; CT, connective tissue; MU, muscle.

2. Transcriptional regulation by TR and its dual functions in Xenopus development

Extensive in vitro and in vivo studies have shown that the T3 nuclear receptors (TRs) mediate the major biological effects of T3 (Buchholz, Paul, Fu, & Shi, 2006; Forrest, 1994; Laudet & Gronemeyer, 2002; Lazar, 1993; Shi, Wong, Puzianowska-Kuznicka, & Stolow, 1996; Yen, 2001). TRs are encoded by two highly conserved TR genes, TRα and TRβ genes, in all vertebrates, including the diploid anuran Xenopus tropicalis and pseudo-tetraploid anuran Xenopus laevis, which has two duplicated TRα and TRβ genes (Laudet & Gronemeyer, 2002; Shi, Yaoita, & Brown, 1992; Wang, Matsuda, & Shi, 2008; Yaoita, Shi, & Brown, 1990). TRs regulates target gene transcription in a T3-dependent manner. For T3-inducible genes, they bind to T3 response elements (TREs) in the target genes as heterodimers with 9-cis retinoic acid receptors (RXRs) to repress their transcription in the absence of T3 and activate them when T3-bound by recruiting corepressor and coactivator complexes, respectively (Bulynko & O’Malley, 2011; Grimaldi, Buisine, Miller, Shi, & Sachs, 2013; McKenna et al., 2009; O’Malley, Malovannaya, & Qin, 2012; Perissi, Jepsen, Glass, & Rosenfeld, 2010; Shi, Matsuura, Fujimoto, Wen, & Fu, 2012).

Frog development offers an opportunity to study the developmental functions of both unliganded and liganded TRs. During premetamorphosis, TRs, especially TRα, are expressed but there is little T3 (Kanamori & Brown, 1992; Leloup & Buscaglia, 1977; Shi et al., 1992; Wang & Brown, 1993; Wong & Shi, 1995; Yaoita & Brown, 1990), suggesting that most TRs are likely unliganded and function as repressors of T3-inducible genes to prevent premature metamorphosis (Fig. 2). During metamorphosis, T3 level rises due to endogenous synthesis, causing TRs to be liganded, thereby activating T3-inducible genes to cause metamorphosis (Fig. 2). Thus, TRs have dual functions during frog development (Sachs et al., 2000). Indeed, extensive genetic studies have supported such a dual function model. Earlier studies include transient and transgenic overexpression of wild type or mutant TRs in Xenopus laevis, demonstrating that blocking TR function inhibits T3-inducible gene expression and metamorphosis while enhancing TR function upregulates T3 target genes and accelerate metamorphosis (Buchholz et al., 2006; Buchholz, Hsia, Fu, & Shi, 2003; Buchholz, Tomita, Fu, Paul, & Shi, 2004; Das, Schreiber, Huang, & Brown, 2002; Nakajima & Yaoita, 2003; Puzianowska-Kuznicka, Damjanovski, & Shi, 1997; Schreiber & Brown, 2003; Schreiber, Das, Huang, Marsh-Armstrong, & Brown, 2001). The roles of endogenous TRα and TRβ have also been revealed through gene knockout studies in the diploid Xenopus tropicalis (Buchholz & Shi, 2018; Choi et al., 2015; Choi, Ishizuya-Oka, & Buchholz, 2017; Nakajima, Tanizaki, Luu, Zhang, & Shi, 2020; Nakajima, Tazawa, & Shi, 2019; Nakajima, Tazawa, & Yaoita, 2018; Sachs, 2015; Sakane et al., 2018; Shi, 2021; Shibata et al., 2021; Shibata, Tanizaki, & Shi, 2020; Shibata, Wen, Okada, & Shi, 2020; Tanizaki, Shibata, Zhang, & Shi, 2021, 2022; Tanizaki, Zhang, Shibata, & Shi, 2022; Wen et al., 2017; Wen & Shi, 2015, 2016; Yen, 2015). These studies not only support the dual functions of TR during development but also offer details on TR-subtype-specific and developmental stage- and organ-dependent functions of TRs in regulating metamorphic timing and rate. As predicted by the dual function model, premetamorphic tadpoles lacking both TRα and TRβ fail to respond to exogenous T3, and initiate metamorphosis prematurely relative to wild type siblings, but fail to complete metamorphosis (Shibata, Wen, et al., 2020). Interestingly, many adult organs appear to form in the absence of any TRs and the tadpoles can develop up to the climax of metamorphosis, while larval tissue resorption is inhibited, likely contributing to the death of the TR-double knockout animals at the climax of metamorphosis (Shi, 2021; Shibata, Wen, et al., 2020).

Fig. 2.

Fig. 2

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Dual function of TR during Xenopus metamorphosis. TR can repress and activate T3-inducible genes in the absence and presence of T3, respectively. The presence of little or no T3 in premetamorphic tadpoles enables most or all TRs remaining in the unliganded state and TR/RXR heterodimers recruit HDAC-containing corepressors complexes to target genes. This in turn reduces the levels of activation histone marks and increases the levels of repression histone marks, resulting in gene repression. With rising levels of T3 during metamorphosis, TRs become T3-bound and TR/RXR heterodimers recruit coactivator complexes. This then causes chromatin remodeling, including the loss of 2–3 nucleosomes around the TRE and histone modifications, particularly an increase in activation histone marks and a decrease in repression histone marks, and eventually transcriptional activation. N-CoR, nuclear corepressor; HDAC, histone deacetylase; SRC3, steroid receptor coactivator 3; p300, a histone acetyltransferase; PRMT1, protein arginine methyltransferase 1.

3. A role of histone acetylation in gene regulation by TR

For T3-inducible genes, TR/RXR heterodimers bind to TREs in the target genes to repress their transcription in the absence of T3 and activate them when liganded by recruiting corepressor and coactivator complexes, respectively (Bulynko & O’Malley, 2011; Grimaldi, Buisine, Miller, et al., 2013; McKenna et al., 2009; O’Malley et al., 2012; Perissi et al., 2010; Shi et al., 2012). The best-studied TR-corepressor complexes are those containing either one of the two highly related proteins N-CoR (nuclear corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). These complexes also contain histone deacetylases such as HDAC3 (Burke & Baniahmad, 2000; Chen & Evans, 1995; Glass & Rosenfeld, 2000; Guenther et al., 2000; Horlein et al., 1995; Ishizuka & Lazar, 2003; Jones, Sachs, Rouse, Wade, & Shi, 2001; Jones & Shi, 2003; Li et al., 2000, 2002; Perissi et al., 2010; Stewart, Li, & Wong, 2005; Stewart, Tomita, Shi, & Wong, 2006; Tomita, Buchholz, & Shi, 2004; Yoon et al., 2003; Zhang, Kalkum, Chait, & Roeder, 2002; Zhang & Lazar, 2000). On the other hand, many coactivator complexes have histone acetyltransferase activities. In particular, the steroid receptor coactivators (SRCs: SRC1, SRC2, and SRC3), which bind liganded TR directly and have histone acetyltransferase activities, form large complexes that contain histone acetyltransferases p300/CBP, and the histone methyltransferases PRMT1 and CARM1 (Chakravarti et al., 1996; Chen et al., 1997, 1999; Demarest et al., 2002; Hong, Kohli, Trivedi, Johnson, & Stallcup, 1996; Koh, Chen, Lee, & Stallcup, 2001; Li, Gomes, & Chen, 1997; Li, O’Malley, & Wong, 2000; Ogryzko, Schiltz, Russanova, Howard, & Nakatani, 1996; Onate, Tsai, Tsai, & O’Malley, 1995; Sheppard, Harries, Hussain, Bevan, & Heery, 2001; Takeshita, Cardona, Koibuchi, Suen, & Chin, 1997; Voegel et al., 1998; Voegel, Heine, Zechel, Chambon, & Gronemeyer, 1996). Thus, histone acetylation like plays a critical role in target gene regulation by T3 during amphibian metamorphosis.

Indeed, analyses of in vivo histone acetylation levels at T3-induced genes by using chromatin immunoprecipitation (ChIP) assay with antibodies against acetylated histones have revealed that treatment of premetamorphic Xenopus tadpoles with T3 or an HDAC inhibitor increases histone acetylation, mimicking that during frog metamorphosis (Matsuura, Fujimoto, Fu, & Shi, 2012; Sachs, Amano, Rouse, & Shi, 2001; Sachs, Amano, & Shi, 2001; Sachs & Shi, 2000). Furthermore, treatment of premetamorphic tadpoles with a histone deacetylase inhibitor also upregulates T3 response genes in the absence of T3, resembling T3 treatment, although it does not induce metamorphosis (Sachs, Amano, Rouse, & Shi, 2001; Sachs, Amano, & Shi, 2001). In addition, ChIP assays with antibodies against corepressors have revealed that TRs recruit corepressor complexes to T3-target genes in different organs of premetamorphic Xenopus laevis tadpoles (Buchholz et al., 2003; Sachs et al., 2002; Tomita et al., 2004), and transgenic overexpression of a dominant negative form of the corepressor N-CoR containing only the TR-interacting domain causes precocious upregulation of T3-target genes and initiation of metamorphosis in Xenopus laevis (Sato, Buchholz, Paul, & Shi, 2007). Such findings support an important role of histone deacetylation in gene repression via recruitment of HDAC-containing corepressor complexes by unliganded TR in premetamorphic tadpoles and are consistent with the dual function model of TR in development.

4. Critical involvement of steroid-receptor coactivator complexes in regulating metamorphosis by liganded TR

The dual function model for TR implies that during metamorphosis when T3 is present, liganded TR recruits coactivator complexes. Indeed, ChIP assays have shown that at least the complexes containing histone acetyltransferases SRC3 and p300 and histone methyltransferase PRMT1 (protein arginine methyltransferase 1) are recruited by TR during natural or T3-induced metamorphosis (Havis, Sachs, & Demeneix, 2003; Matsuda, Paul, Choi, Hasebe, & Shi, 2009; Paul, Buchholz, Fu, & Shi, 2005, 2007; Paul, Fu, Buchholz, & Shi, 2005). This is accompanied by increased local histone acetylation at the T3-target genes and upregulation of target gene expression.

Of particular interest among the coactivators is the TR-binding histone acetyltransferase SRC3. During Xenopus laevis development, SRC3 is upregulated by T3 and more importantly recruited by liganded TR in a gene- and tissue-specific manner (Paul, Buchholz, et al., 2005; Paul & Shi, 2003). A functional role of SRC3-containing coactivator complexes in frog metamorphosis was first demonstrated by transgenic studies with a dominant negative form of Xenopus laevis SRC3 (F-dnSRC3) (Paul, Fu, et al., 2005). F-dnSRC3 contains only the TR-binding domain of SRC3 (Fig. 3) and its binding to liganded TR is expected to prevent the formation of a normal functional coactivator complex due to the lack of other domains, such as the one binding to the histone acetyltransferase p300. In addition, it will also compete against the binding of other coactivators, including the endogenous wild type SRC3, to liganded TR during metamorphosis, thus inhibiting coactivator recruitment by liganded TR.

Fig. 3.

Fig. 3

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Transgenic overexpression of a Flag-tagged dominant negative steroid receptor coactivator 3 (F-dnSRC3) inhibits metamorphosis. (A) A schematic representation of the full-length SRC3. bHLH/PAS, basic helix–loop–helix and PAS dimerization domains; RID, receptor interaction domain; CID, CBP/p300 interaction domain. The LXXLL motifs present in the protein are numbered from i to vi. A glutamine (Q)-rich region is present toward the C-terminal end of the protein. The Flag-tagged dominant negative form (F-dnSRC3) used in transgenesis is shown below the full length SRC3. It covers aa 600 to aa 751, which comprise the LXXLL motifs i to iii, forming the RID and fused to an N-terminal peptide containing the Flag tag and nuclear localization sequences. (B) Transgenic expression of F-dnSRC3 does not affect T3-induced release of corepressor SMRT but inhibits the recruitment of endogenous wild type SRC3 to the T3-regulated TH/bZIP promoter, thus reducing histone acetylation. Wild type (WT) and transgenic (Tg) animals at stage 54 were treated with 10 nM T3 for 2 days. Intestinal nuclei were isolated and ChIP assays performed by using anti-SRC3 (for endogenous wild type SRC3), anti-acetylated histone H4 (AcH4), anti-SMRT (for endogenous corepressor SMRT), and anti-Flag (for transgenic F-dnSRC3) antibodies. The TRE region of the T3-response gene TH/bZIP was analyzed by real time PCR after immunoprecipitation with the indicated antibodies. Note that F-dnSRC3 was recruited to the promoter upon T3-treatment, competing against the recruitment of endogenous SRC3 recruitment and reducing local AcH4 level in the transgenic animals. (C) F-dnSRC3 inhibits metamorphosis. Wild type (a) and transgenic Xenopus laevis tadpoles (b) at stage 54 after treatment with 5 nM T3 for 3 days, with the resorption of gills and development of the Meckel’s cartilage (leading to protrusion of the jaw) in the wild type but not transgenic tadpole after T3 treatment. (c) A transgenic tadpole which failed to undergo tail resorption during natural development and eventually died. See Paul, Fu, et al. (2005) for more details.

Indeed, transgenic overexpression of F-dnSRC3 in Xenopus laevis inhibited the recruitment of endogenous wild type SRC3 to the promoter regions of T3-target genes, but expectedly did not influence the release of corepressors in the presence of T3 (Fig. 3) (Paul, Fu, et al., 2005). Furthermore, it also reduced histone acetylation at target gene promoters and T3-induction of target gene expression (Paul, Fu, et al., 2005). Most importantly, the expression of F-dnSRC3 delayed/inhibited both T3-induced and natural metamorphosis (Fig. 3) (Paul, Fu, et al., 2005). Some of the transgenic animals developed to the climax of metamorphosis but failed to complete tail resorption and eventually died (Fig. 3) (Paul, Fu, et al., 2005). These phenotypes resemble those of Xenopus tropicalis animals with both TR genes knocked out (Shi, 2021; Shibata, Wen, et al., 2020), highlighting the importance of liganded TR to recruit coactivators to ensure proper rate of metamorphic progression and complete resorption of larval tissues.

Since F-dnSRC3 is expected to compete against the binding of all TR-interacting coactivators, not just SRCs, by liganded TR, the transgenic studies with F-dnSRC3 suggest but do not prove that SRC-containing complexes are critical for metamorphosis. On the other hand, a separate transgenic study with a dominant negative form of p300, which binds to SRC to form a large coactivator complex, provided strong evidence for an essential role of SRC-containing complexes during Xenopus laevis metamorphosis (Paul et al., 2007). This dominant negative p300 contained only the domain that binds to SRCs. It can bind to SRCs but does not affect the direct binding of liganded TR to any coactivators, including SRC3. However, the lack of other domains in p300 prevents the formation of a functional SRC-containing coactivator complex when the dominant negative p300 binds to SRCs. When this dominant negative p300 was overexpressed in transgenic Xenopus laevis tadpoles, it inhibited the recruitment of endogenous wild type p300 to T3-target promoters by liganded TR and reduced local histone acetylation and gene activation (Paul et al., 2007). More importantly, it also delayed/inhibited both T3-induced and natural metamorphosis, resembling the effects of the transgenic expression of F-dnSRC3. These observations indicate that coactivator complexes containing SRC-p300 are essential for the control of amphibian metamorphosis by liganded TR.

Studies on yet another component of the SRC-p300 complexes, PRMT1, a histone arginine methyltransferase, provides further support for the critical role of such complexes in TR function during metamorphosis. PRMT1 was found to be recruited by TR in a T3-dependent manner to T3 target genes during Xenopus laevis metamorphosis (Matsuda et al., 2009). More importantly, transgenic overexpression of wild type PRMT1 enhanced TR function, including increased binding of TR to endogenous target genes and increased gene activation by T3 (Matsuda et al., 2009). It also accelerated metamorphic progression (Matsuda et al., 2009). These findings thus support a role of SRC-containing coactivator complexes in regulating the rate of metamorphosis by liganded TR.

With the development of gene-editing technologies that can knockout genes in Xenopus laevis and tropicalis (Lei et al., 2013; Shi et al., 2015; Wang et al., 2015), it has become possible to investigate the role of endogenous cofactors during metamorphosis. Indeed, the SRC3 gene was recently knocked out in Xenopus tropicalis by using CRISPR-mediated gene knockout technology (Tanizaki, Bao, Shi, & Shi, 2021). Consistent with SRC3 being a histone acetyltransferase, knocking SRC3 resulted in a reduction in overall histone acetylation in tadpoles (Fig. 4). Interestingly, removing both copies of the endogenous SRC3 gene had little effect on either the external morphology of the animals or overall developmental rate, with all three genotypes (wild type, SRC heterozygous and homozygous) completing metamorphosis (when tail is completely resorbed) at similar ages (Tanizaki, Bao, et al., 2021). On the other hand, there was a delay in the remodeling of the animal intestine, where SRC3 is upregulated during metamorphosis (Paul & Shi, 2003), accompanied by reduced expression of T3 target genes in the intestine at the climax of metamorphosis (Fig. 4) (Tanizaki, Bao, et al., 2021). Furthermore, when premetamorphic tadpoles were treated with physiological concentration of T3 to induce precocious metamorphosis, the SRC3 knockout caused a delay as reflected by the morphology of the hindlimbs, which is one of the first and the most T3-sensitive morphological changes during metamorphosis (Fig. 4). In addition, intestinal remodeling induced by T3 was also delayed/inhibited by the SRC3 knockout, including reduced apoptosis of larval epithelial cells and adult intestinal stem cell proliferation (Fig. 4) (Tanizaki, Bao, et al., 2021). Thus, endogenous SRC3 is important for temporal control of metamorphosis by functioning as a TR coactivator.

Fig. 4.

Fig. 4

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SRC3 knockout reduces histone H4 acetylation and inhibits T3-induced metamorphosis. (A)/(B) Western blots showing that homozygous SRC3 knockout tadpoles have no detectable SRC3 protein and reduced histone H4 acetylation. Total protein was isolated from whole body of wild type (WT), heterozygous (SRC3+/−), and compound heterozygous (functionally homozygous, SRC3−/−) SRC3 mutant tadpoles at stage 46 and subjected to Western blot analyses with antibodies against SRC3, acetyl-histone H4, or histone H4 (A). The signal intensity of the bands was measured by image j and presented as the mean ± standard deviation of n = 3 (B). Statistical analysis: ANOVA one-way followed by Tukey analysis. *P <0.05. (C) SRC3 knockout reduces gene activation by T3 in the intestine. The intestine was isolated from wild type (WT), SRC3+/− and SRC3−/− tadpoles at stage 54 with or without 18 h T3 treatment before RNA isolation and qRT-PCR analysis of the indicated TR target genes. **P < 0.01 for T3 treated vs. WT intestine. (D) SRC knockout inhibits T3-induced limb metamorphosis. Wild type (WT) and SRC3 knockout (SRC3−/−) tadpoles at stage 54 were treated with 10 nM T3 for 3 days at 25°C and hindlimb region was photographed. The lower panels were the same as the top panels except the added white line marking the approximate boundary of the outer limb epithelium and/or the boundaries of the digits (white arrowheads indicate some of the digits of the wild type animal treated with T3). (E) Adult intestinal epithelium development is inhibited by SRC3 knockout. Cross-sections of the intestine in WT and SRC3−/− tadpoles as in (D) were stained with methyl green-pyronin Y (staining DNA blue and RNA red). Note that the adult epithelium folds began to form after 3 days of T3 treatment in WT but not SRC3−/− tadpoles. See Tanizaki, Bao, et al. (2021) for more details.

5. Conclusion

The biphasic nature of amphibian metamorphosis has long made it an excellent model to study postembryonic development in vertebrates, particularly regarding the roles of T3 and TRs in tissue maturation and remodeling. The recent advancement in molecular and genetic tools has further enhanced the value of the Xenopus model (Brown & Cai, 2007; Buchholz, 2015; Buchholz & Shi, 2018; Grimaldi, Buisine, Bilesimo, & Sachs, 2013; Shi, 2013b, 2021; Shi et al., 2012). Studies on amphibian metamorphosis has revealed dual involvement of TR in development, in the unliganded form, before sufficient T3 is available, to repress T3-inducible genes and thus prevent premature adult organ development, and later in the liganded state to activate target genes and ensure metamorphosis of different organs/tissues. Such metamorphic changes share many conserved features with postembryonic mammalian development (Buchholz & Shi, 2018; Sachs & Buchholz, 2017; Shi, 2021). Furthermore, the dependence of metamorphosis in everyone organ/tissue on T3 in anurans has made it possible to investigate the roles of TR-binding cofactors in metamorphosis. While many of the cofactors are involved in signaling by different hormones, no hormone other than T3 has such a necessary and sufficient effect on anuran metamorphosis, making it easy to correlate the effects of altering any cofactors on metamorphosis with the role of such cofactors in TR signaling. The studies on SRC3 during Xenopus metamorphosis have provided some of the strongest pieces of evidence for SRC-containing histone acetyltransferase complexes in the regulation of vertebrate development by any nuclear hormone receptors. Interestingly, inhibiting SRC-complex function via transgenic expression of a dominant negative SRC3 has much bigger effects than knocking out SRC3 during Xenopus metamorphosis, likely reflecting redundancies among SRC3 family members or among different TR-binding coactivators during Xenopus development. This appears to be quite similar to findings in mouse knockout studies. SRC3 knockout in mouse also has only mild effects, including retarded growth and development, and decreased reproductive function (Xu et al., 2000), and SRC1 knockout has even less effect (Xu et al., 1998). In contrast, double knockout of both SRC1 and SRC3 in mouse causes embryonic lethality (Chen, Liu, & Xu, 2010), highlighting SRC redundancies and compensation during development. Such findings support evolutional conservations in the function of SRC-containing histone acetyltransferase complexes and the validity of the anuran model for studying the roles of such complexes in postembryonic vertebrate development.

Acknowledgment

This research in the authors’ laboratory was supported by the intramural Research Program of NICHD, NIH.

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