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. Author manuscript; available in PMC: 2025 Jul 17.
Published in final edited form as: Vitam Horm. 2021 Mar 9;116:269–293. doi: 10.1016/bs.vh.2021.02.010

The development of adult intestinal stem cells: Insights from studies on thyroid hormone-dependent anuran metamorphosis

Yun-Bo Shi 1,*, Yuki Shibata 1, Yuta Tanizaki 1, Liezhen Fu 1
PMCID: PMC12268621  NIHMSID: NIHMS2093537  PMID: 33752821

Abstract

Vertebrates organ development often takes place in two phases: initial formation and subsequent maturation into the adult form. This is exemplified by the intestine. In mouse, the intestine at birth has villus, where most differentiated epithelial cells are located, but lacks any crypts, where adult intestinal stem cells reside. The crypt is formed during the first 3 weeks after birth when plasma thyroid hormone (T3) levels are high. Similarly, in anurans, the intestine undergoes drastic remodeling into the adult form during metamorphosis in a process completely dependent on T3. Studies on Xenopus metamorphosis have revealed important clues on the formation of the adult intestine during metamorphosis. Here we will review our current understanding on how T3 induces the degeneration of larval epithelium and de novo formation of adult intestinal stem cells. We will also discuss the mechanistic conservations in intestinal development between anurans and mammals.

1. Introduction

Thyroid hormone (T3) is critical for not only the physiology and function of many adult organs but also their development, especially the maturation into the adult form during vertebrate postembryonic development when plasma T3 level peaks. This period corresponds to several weeks or months around birth in mouse and human, respectively (Shi, 1999; Tata, 1993). The maternal dependence of newborns/neonates and uterus-enclosed nature of the embryos in mammals has made it difficult to study how T3 functions during postembryonic development or how adult organs are formed during this period. Interestingly, this period resembles amphibian metamorphosis. In anurans Xenopus laevis, T3 is low or not detectable before stage 54, about 4 weeks old and the onset of metamorphosis, reaches the peak level around stage 62 (about 7 weeks old), and drops to a lower, adult level by the end of metamorphosis (about 8 weeks old or stage 66) (Leloup & Buscaglia, 1977; Nieuwkoop & Faber, 1965). The high levels of T3 during this period triggers the transformations of essentially every organ/tissue in the tadpole. These changes include de novo formation of adult organs such as limbs, total degeneration of larval specific organs such as the tail and gills, and drastic remodeling of most organs, including the intestine, from the larval forms into their adult forms (Dodd & Dodd, 1976; Shi, 1999; Tata, 1993). Many of these changes resemble what happen during mammalian postembryonic development (Shi, 1999; Tata, 1993). Importantly, anuran metamorphosis can be easily manipulated by controlling the availability of T3 to tadpoles or even organ or primary cell cultures, making anuran metamorphosis a highly valuable model for studying T3 action and organ maturation during postembryonic development in vertebrates. This is further enhanced by the recent development of transgenic and gene-editing technologies suitable for genetic studies in the highly related anuran species Xenopus laevis and tropicalis (Blitz, Biesinger, Xie, & Cho, 2013; Fu, Buchholz, & Shi, 2002; Kroll & Amaya, 1996; Lei, Guo, Deng, Chen, & Zhao, 2013; Lei et al., 2012; Nakade et al., 2014; Nakayama et al., 2013; Shi et al., 2015; Wang et al., 2015; Young et al., 2011).

2. T3 and intestinal stem cell development

The vertebrate intestine has long been used as a model system for investigating the property and function of adult stem cells in vertebrates. Organ-specific adult stem cells are essential for organ homeostasis and function (Bao, Shi, & Shi, 2020; Clevers, 2013; Shi, Hasebe, Fu, Fujimoto, & Ishizuya-Oka, 2011; Sirakov, Kress, Nadjar, & Plateroti, 2014; Sun, Fu, & Shi, 2014; Sun & Shi, 2012; van der Flier & Clevers, 2009). In adult mammalian intestine, epithelial stem cells are located at the bottom of the crypts (Fig. 1). After proliferation, their daughter cells migrate along the crypt-villus axis and differentiate into different types of epithelial cells. The differentiated epithelial cells eventually die via programmed cell death, mostly at the villus tip. Such a self-renewing cycle occurs once every 1–6 days in adult mammals (MacDonald, Trier, & Everett, 1964; Toner, Carr, & Wyburn, 1971; van der Flier & Clevers, 2009) and every 2 weeks in the anuran Xenopus laevis (McAvoy & Dixon, 1977).

Fig. 1.

Fig. 1

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Intestinal maturation takes place during postembryonic development in vertebrates. Both mouse intestinal maturation (upper panel) and frog intestinal remodeling during Xenopus metamorphosis (lower panel) involve the formation of adult epithelial stem cells. Some of the pre-existing epithelial cells develop into adult stem cells during the period when plasma thyroid hormone (T3) levels are high. In mouse, intervillus, sonic hedgehog (hh)-expressing epithelial cells develop into stem cells that express both hh and protein arginine methyltransferase 1 (PRMT1) in the newly formed intestinal crypts within the first 3 weeks after birth. The Xenopus adult intestinal stem cells are formed during metamorphosis through dedifferentiation of some larval epithelial cells to also express high levels of PRMT1 and Shh. The adult stem cell markers LGR5 and Msi1 are expressed in the developing adult intestinal stem cells at the climax of metamorphosis, although they have not been analyzed in the maturing neonatal mouse intestine. Modified after Ishizuya-Oka, A., & Shi, Y.B. (2011). Evolutionary insights into postembryonic development of adult intestinal stem cells. Cell & Bioscience 1, 37.

While there have been extensive studies on the adult intestinal stem cells in mammals, revealing interesting properties of and molecular pathways important for adult intestinal stem cells (Sancho, Eduard Batlle, & Clevers, 2004; van der Flier & Clevers, 2009), much less is known about their development. Recent studies have suggested that the formation of mouse adult intestinal stem cells occurs during the neonatal period when plasma thyroid hormone (T3) level peaks (Fig. 1) (Harper, Mould, Andrews, Bikoff, & Robertson, 2011; Matsuda & Shi, 2010; Muncan et al., 2011; Sun & Shi, 2012). In addition, mutations in T3 receptors (TRs) and deficiency in T3 or TR in mouse cause intestinal defects, including reduced cell proliferation (Bao et al., 2019; Flamant et al., 2002; Kress, Rezza, Nadjar, Samarut, & Plateroti, 2009; Plateroti et al., 1999, 2001; Plateroti, Kress, Mori, & Samarut, 2006). Thus, it is very likely that T3 regulates adult intestinal stem cell development during intestinal maturation.

Similarly, the adult frog intestine is formed during T3-dependent amphibian metamorphosis (Dodd & Dodd, 1976; Shi, 1999; Tata, 1993). In premetamorphic tadpoles, the intestine consists of mainly a monolayer of larval epithelial cells with a single epithelial fold, the typhlosole, surrounded by thin layers of connective tissue and muscles (Figs. 1 and 2) (Shi & Ishizuya-Oka, 1996; Sterling, Fu, Matsuura, & Shi, 2012). As T3 level rises during metamorphosis, most larval epithelial cells undergo apoptosis but some, through yet unknown mechanisms, undergoes dedifferentiation to be highly proliferative cells expressing well-known adult intestinal stem cell markers including leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) and Musashi-1 (Msi-1) (Figs. 1 and 2) (Ishizuya-Oka, Shimizu, Sakakibara, Okano, & Ueda, 2003; Okada, Wen, Miller, Su, & Shi, 2015; Wen, Hasebe, Miller, Ishizuya-Oka, & Shi, 2015). By the end of metamorphosis, the proliferating cells differentiate to form a multiply folded adult epithelium surrounded by thick layers of connective tissue and muscles. Accompanying these changes is drastic reduction in the length of the intestine (Ishizuya-Oka et al., 2009; Schreiber, Cai, & Brown, 2005; Shi et al., 2011; Shi & Ishizuya-Oka, 1996; Sterling et al., 2012). In the adult frog, the intestinal stem cells are localized in the trough of the epithelial fold while cell death occurs mainly at the crest of the fold, resembling those occurring in the mammalian crypt-villus unit (Ishizuya-Oka & Shi, 2011; Shi et al., 2011; Shi & Ishizuya-Oka, 1996). Importantly, like all other events during anuran metamorphosis, intestinal remodeling, including adult epithelial stem cell formation, requires T3 signaling. Blocking the synthesis of endogenous T3 in tadpoles inhibits metamorphosis, including intestinal remodeling (Gilbert, Tata, & Atkinson, 1996; Shi, 1999). On the other hand, T3-treatment of premetamorphic tadpoles or even intestinal organ cultures results in premature intestinal metamorphosis, including larval epithelial cell death and de novo formation of adult stem cells (Shi & Ishizuya-Oka, 1996). Thus, T3 controls the de novo formation of the adult epithelial stem cells, which originate organ-autonomously within the larval intestine. Furthermore, T3 treatment of recombinant organ cultures made of wild type intestinal epithelium and transgenic non-epithelial tissues (the rest of the intestine) expressing GFP results in adult epithelium lacking GFP expression while GFP positive adult stem cells are produced if the transgenic epithelium expressing GFP is used in combination with either wild type or transgenic non-epithelial tissues in the organ cultures, demonstrating the epithelial origin of the adult stem cells (Ishizuya-Oka et al., 2009). Given the lack of epithelial stem cells in the tadpole intestine and the differentiated larval epithelial cells are capable of proliferation (Ishizuya-Oka & Shi, 2008; Shi & Ishizuya-Oka, 1996), T3 appears to induce the dedifferentiation of some larval epithelial cells into adult stem cells.

Fig. 2.

Fig. 2

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Proliferating adult epithelial stem cells are formed de novo at the climax of Xenopus metamorphosis. Edu (5-ethynyl-2′-deoxyuridine, labeling newly synthesized DNA) were injected into tadpoles at premetamorphic stage 54 (A), metamorphic climax (B, stage 62), or the end of metamorphosis (C, stage 66) to label proliferating cells. One hour later, the animals were sacrificed for preparation of intestinal cross-sections, which were then double-stained for EdU and differentiated intestinal epithelial cell marker IFABP (intestinal fatty acid binding protein) by immunohistochemistry. The epithelium-mesenchyme boundary is marked by dotted lines. Note that at the climax, high levels of EdU-labeled, IFABP-negative proliferating cells were present as clusters between the connective tissue and differentiated cells expressing IFABP (B). After metamorphosis, the proliferating cells were in the troughs where IFABP was low (C), mimicking that in the adult mammalian crypt. Modified after Okada, M., Wen, L., Miller, T.C., Su, D., & Shi, Y.B. (2015). Molecular and cytological analyses reveal distinct transformations of intestinal epithelial cells during Xenopus metamorphosis. Cell & Bioscience 5, 74.

3. Gene regulation by TR and its roles during anuran metamorphosis

T3 is believed to function mainly through its genomic effects via binding to T3 receptors (TRs), although it also has non-genomic effects, at least in cell cultures (Buchholz, Paul, Fu, & Shi, 2006; Davis & Davis, 1996; Evans, 1988; Laudet & Gronemeyer, 2002; Lazar, 1993; Shi, 1999; Tsai & O’Malley, 1994; Yen, 2001). All vertebrates have two TR genes, TRα and TRβ. Extensive biochemical and molecular studies in vitro and in cell cultures have shown that both TRs can activate or repress the transcription of T3-inducible genes in the presence or absence of T3 respectively. TRs do so by mainly functioning as heterodimers with 9-cis retinoic acid receptors (RXRs) to bind to specific DNA sequences called T3-response elements (TREs) within target genes (Lazar, 1993; Mangelsdorf et al., 1995; Tsai & O’Malley, 1994; Wong et al., 1998; Wong, Shi, & Wolffe, 1995, 1997; Yen, 2001). Unliganded TR can recruit corepressor complexes containing histone deacetylases to the target genes to repress their expression (Chen & Evans, 1995; Horlein et al., 1995; Jones, Sachs, Rouse, Wade, & Shi, 2001; Jones & Shi, 2003; Li et al., 2002; Perissi, Jepsen, Glass, & Rosenfeld, 2010; Stewart, Li, & Wong, 2005; Stewart, Tomita, Shi, & Wong, 2006; Tomita, Buchholz, & Shi, 2004; Yoon et al., 2003), while liganded TRs recruit coactivator complexes such as those containing histone acetyltransferases and histone methyltransferases to activate transcription, likely via epigenetic modifications of histones and chromatin remodeling (Bulynko & O’Malley, 2011; Demarest et al., 2002; O’Malley, Malovannaya, & Qin, 2012; Sheppard, Harries, Hussain, Bevan, & Heery, 2001; Shi, Matsuura, Fujimoto, Wen, & Fu, 2012; Yen, 2001). These properties have led to a dual function model for TRs during amphibian metamorphosis (Sachs et al., 2000). That is, during premetamorphosis, TRs are mainly in the unliganded state when T3 is absent or at low levels, and thus recruit corepressors to repress T3-inducible genes. This helps to prevent precocious initiation of metamorphosis to ensure a proper growth period prior to metamorphosis. When T3 levels rise during metamorphosis, T3 binds to TR, which in turn releases the corepressors and recruit coactivators, leading to the de-repression and further activation of the T3-inducible genes, thus triggering metamorphic transformations of different tissues and organ.

With the development of chromatin immunoprecipitation (ChIP) assays and genetic tools for in vivo studies, we and others have tested this dual function model and investigated the roles of TRs during Xenopus metamorphosis. Indeed, TR and RXR have been found to be associated with T3-inducible genes in pre- and metamorphosing Xenopus laevis and tropicalis tadpoles (Sachs & Shi, 2000; Wang, Matsuda, & Shi, 2008) and recruits corepressors or coactivators to modify histones and remodel chromatin in the absence or presence of T3, respectively (Bilesimo et al., 2011; Bulynko & O’Malley, 2011; Demarest et al., 2002; Grimaldi, Buisine, Miller, Shi, & Sachs, 2013; Havis, Sachs, & Demeneix, 2003; Heimeier, Hsia, & Shi, 2008; Huang, Li, Sachs, Cole, & Wong, 2003; Matsuda, Paul, Choi, Hasebe, & Shi, 2009; Matsuda, Paul, Choi, & Shi, 2007; Matsuura, Fujimoto, Fu, & Shi, 2012; O’Malley et al., 2012; Paul, Buchholz, Fu, & Shi, 2005, 2007; Paul, Fu, Buchholz, & Shi, 2005; Sachs, Amano, Rouse, & Shi, 2001; Sachs, Amano, & Shi, 2001; Sachs et al., 2002; Sachs & Shi, 2000; Sheppard et al., 2001; Shi et al., 2012; Tomita et al., 2004; Wang et al., 2008; Wen, Fu, & Shi, 2017; Yen, 2001). More importantly, genetic studies have now demonstrated that TRs are necessary and sufficient for T3-dependent amphibian metamorphosis. First, transgenic expression of dominant negative mutant TRs that cannot bind to T3 inhibits Xenopus laevis metamorphosis while heat shock-inducible transgenic expression of a dominant positive TR that does not bind to T3 but functions like liganded TR mimics T3 induction of metamorphosis in wild type tadpoles, indicating that TR is sufficient to mediate most if not all effects of T3 during amphibian metamorphosis (Bagamasbad, Howdeshell, Sachs, Demeneix, & Denver, 2008; Brown & Cai, 2007; Buchholz et al., 2006; Buchholz, Hsia, Fu, & Shi, 2003; Buchholz, Tomita, Fu, Paul, & Shi, 2004; Denver, Hu, Scanlan, & Furlow, 2009; Nakajima & Yaoita, 2003; Sachs et al., 2000; Schreiber, Das, Huang, Marsh-Armstrong, & Brown, 2001; Schreiber, Mukhi, & Brown, 2009; Shi, 1994, 2009). More recently, with the adaptation of gene-editing technologies to knockout endogenous genes in the diploid Xenopus tropicalis, we and others have shown that both TRα and TRβ are important for metamorphosis (Buchholz & Shi, 2018; Choi, Ishizuya-Oka, & Buchholz, 2017; Choi et al., 2015; Nakajima, Tazawa, & Shi, 2019; Nakajima, Tazawa, & Yaoita, 2018; Sachs, 2015; Sakane et al., 2018; Shibata, Tanizaki, & Shi, 2020; Shibata, Wen, Okada, & Shi, 2020; Wen et al., 2017; Wen & Shi, 2015, 2016; Yen, 2015). While animals lacking either TRα or TRβ can complete metamorphosis and develop into mature frogs, they have various developmental abnormalities during metamorphosis, suggesting that TRα and TRβ have distinct roles in coordinating tissue transformation during metamorphosis but nonetheless can compensate for each other during development. When both TR genes are knocked out, the resulting TR double knockout tadpoles initiate metamorphosis earlier (at younger age) and subsequently progress much slower through metamorphosis (Shibata, Wen, et al., 2020). Thus, consistent with the dual function model, de-repression of the T3-inducible genes leads to premature initiation of metamorphosis and that TRs are important for metamorphic progression. Interestingly and surprisingly, tadpoles lacking both TRα and TRβ can develop up to the climax of metamorphosis (stage 61, Fig. 3) (Shibata, Wen, et al., 2020), suggesting that TRs are not required for the initiation of metamorphosis and de-repression of T3 target genes due to the loss of TRs is sufficient for many of the metamorphic processes. On the other hand, compared to wild type tadpoles at stage 61, the tadpoles lacking any TR have larger gills at stage 61 (Fig. 3), suggesting inhibition of gill resorption due to the TR knockout. Furthermore, these TR double knockout tadpoles are stalled at stage 61 for 2 weeks or so and then die, in contrast to the wild type tadpoles at stage 61, which need only about 1 week to complete the remaining metamorphic changes to become tailless froglets. Further analyses suggest that the development of many of the adult tissues/organs can occur or even takes place earlier in the TR double knockout tadpoles compared to the wild type animals, while the resorption of many larval tissues/organs is inhibited due to the lack of TR (Shibata, Wen, et al., 2020). These finding suggest that de-repression of T3 target genes is sufficient for adult organ development while larval tissue degeneration requires gene activation by liganded TR.

Fig. 3.

Fig. 3

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TRs are not required for the initiation of metamorphosis but essential for animal survival and the completion of metamorphosis. TRα and TRβ double knockout (TR-DKO) Xenopus tropicalis tadpoles can develop to the climax stage of 61. Compared to wild type (WT) tadpoles at stage 61, the tadpoles lacking any TR have larger gills, suggesting inhibition of gill resorption due to the TR knockout. Interestingly, these TR-DKO tadpoles are stalled at stage 61 for 2 weeks or so and then die while the WT tadpoles at stage 61 need only about 1 week to complete the remaining metamorphic changes to become tailless froglets. See Shibata, Y., Wen, L., Okada, M., & Shi, Y.B. (2020). Organ-specific requirements for thyroid hormone receptor ensure temporal coordination of tissue-specific transformations and completion of xenopus metamorphosis. Thyroid 30, 300–313 for more details.

4. An essential role of TR in adult intestinal stem cell development

Recent gene knockout studies in Xenopus tropicalis indicate that both TRα and TRβ are important for intestinal metamorphosis (Choi et al., 2015, 2017; Nakajima et al., 2018; Sakane et al., 2018; Shibata, Tanizaki, & Shi, 2020; Shibata, Wen, et al., 2020; Wen & Shi, 2015, 2016; Wen, Shibata, et al., 2017). TRα knockout delays intestinal remodeling (Choi et al., 2017; Wen, Shibata, et al., 2017), while there are only relatively subtle differences in intestinal remodeling between TRβ knockout tadpoles and wild type siblings during natural metamorphosis (Nakajima et al., 2018; Sakane et al., 2018), despite a strong upregulation of TRβ expression during intestinal metamorphosis. These findings suggest that there is a strong compensation between TRα and TRβ during the lengthy natural metamorphosis. This was supported by the recent analysis of intestinal remodeling in TRβ knockout during T3-induced metamorphosis (by treating premetamorphic tadpoles at stage 54 with exogenous but physiological levels of T3), where the larval epithelial cell death and adult intestinal stem cell formation occur within 2–3 days, much shorter than the 2–3 weeks required for the premetamorphic tadpoles at stage 54 to reach stages 60–62 when larval cell death and adult epithelial stem cell formation take place during the natural metamorphosis (Shibata, Tanizaki, & Shi, 2020). Consistent with the reduction in T3-induction of TR target genes in the intestine in TRβ knockout tadpoles, T3-induced reduction in intestinal length, larval epithelial cell death, and adult epithelial stem cell proliferation are all delayed/inhibited in the TRβ knockout tadpoles compared to the wild type siblings. These findings not only reveal a critical role of TRβ for intestinal metamorphosis but also demonstrate that the compensation for the loss of TRβ by TRα is too slow to prevent the defects caused by TRβ knockout during the fast intestinal remodeling induced by T3 treatment.

As described above, TRα and TRβ double knockout animals died at the climax (stage 61) of metamorphosis. Analyses of the intestine have revealed that unlike the wild type intestine at stage 61, little larval epithelial cell death or adult epithelial stem cell proliferation is present in the intestine of TRα and TRβ double knockout animals at stage 61, although adult epithelial folds are formed precociously (Shibata, Y. and Shi, Y.-B., unpublished observation). Furthermore, T3 treatment of premetamorphic TRα and TRβ double knockout animals does not induce any metamorphic changes, including the reduction of intestinal length, accompanied by the lack of the induction of T3 target genes (Shibata, Wen, et al., 2020). Thus, TRs are essential for adult epithelial stem cell development during intestinal remodeling.

A role of TR in adult stem cell development during intestinal metamorphosis has also been supported by recombinant organ culture studies involving animals containing a heat shock-inducible transgenic dominant positive TR (dpTR) that cannot bind to T3 but functions as a constitutively activated TR (Buchholz et al., 2004; Hasebe, Buchholz, Shi, & Ishizuya-Oka, 2011). By recombining wild type intestinal epithelium with transgenic non-epithelium or vice versa, T3 target genes can be selectively activated in either the epithelium or non-epithelium by heat shock treatment of the organ cultures. Analyses of such recombinant organ cultures have shown that dpTR expression in both epithelium and non-epithelium can induce larval epithelial degeneration and development of the adult intestine in the absence of T3, indicating that TR is sufficient for mediating all the effects of T3 for intestinal remodeling (Hasebe et al., 2011). Interestingly, dpTR expression in either the epithelium or non-epithelium can induce larval epithelial cell death, suggesting T3 can induce epithelial apoptosis both cell autonomously and via cell-cell interaction. On the other hand, dpTR in the non-epithelium fails to induce any adult stem cell development while its expression in the epithelium alone leads to the dedifferentiation of some larval epithelial cells, i.e., activating sonic hedgehog gene expression while repressing the expression of the differentiation marker gene encoding intestinal fatty acid binding protein (Hasebe et al., 2011). Interestingly, such dedifferentiated cells lack the expression of Msi-1, a well-known adult intestinal stem cell marker, indicating that adult stem cell development requires T3 signaling in both the epithelium and the non-epithelium (Hasebe et al., 2011). Thus, T3 signaling in the epithelium induces some larval epithelial cells to dedifferentiate and such cells develop further into adult stem cells if T3 signaling is also present in the non-epithelium, which presumably functions to ensure a proper stem cell niche for the developing stem cells (Hasebe et al., 2011; Ishizuya-Oka & Hasebe, 2013; Ishizuya-Oka & Shimozawa, 1992; Schreiber et al., 2009).

5. TR target genes in intestinal stem cell development

TR regulates target gene transcription. Thus, a key to understand how T3 induces the formation of adult stem cells is to identify and functionally characterize TR target genes in the intestine, especially within the epithelium. Over the years, different methods have been used to identify many T3-regulated genes in Xenopus laevis intestine and the involvement of many such genes in intestinal remodeling has been implicated by their expression profiles during metamorphosis (Amano & Yoshizato, 1998; Buchholz, Heimeier, Das, Washington, & Shi, 2007; Fu et al., 2017; Hasebe, Fujimoto, Kajita, & Ishizuya-Oka, 2017; Hasebe, Kajita, Fu, Shi, & Ishizuya-Oka, 2012; Heimeier, Das, Buchholz, Fiorentino, & Shi, 2010; Ishizuya-Oka et al., 2001; Luu et al., 2013; Luu, Fu, Fujimoto, & Shi, 2017; Miller et al., 2013; Na, Fu, Luu, & Shi, 2020; Okada, Miller, Fu, & Shi, 2015; Okada, Miller, Wen, & Shi, 2017; Okada & Shi, 2018a, 2018b; Shi & Brown, 1993; Sun et al., 2013; Sun, Fu, Wen, & Shi, 2014; Wen, Fu, & Shi, 2017). Perhaps not surprisingly, many genes in signaling pathways known to be important for stem cell proliferation and function are induced by T3 during intestinal remodeling. Among them include hedgehog pathway (Hasebe et al., 2012; Hasebe, Kajita, Shi, & Ishizuya-Oka, 2008; Ishizuya-Oka, Ueda, Inokuchi, et al., 2001; Stolow & Shi, 1995; Wen et al., 2015), wnt signaling (Hasebe, Fujimoto, Kajita, & Ishizuya-Oka, 2016; Ishizuya-Oka, Kajita, & Hasebe, 2014; Shi, 2018), Notch pathway (Hasebe et al., 2017), and BMP signaling (Ishizuya-Oka et al., 2001; Ishizuya-Oka, Hasebe, Shimizu, Suzuki, & Ueda, 2006), etc.

If and how such T3-regulated genes participate in adult intestinal stem cell development largely remain to be investigated. Limited genetic studies for some of the genes support their involvement. For example, transgenic overexpression of protein arginine methyltransferase 1 (PRMT1), a known TR coactivator that is upregulated during intestinal remodeling (Fujimoto, Matsuura, Hu-Wang, Lu, & Shi, 2012; Matsuda et al., 2009), leads to increased intestinal stem cells during metamorphosis while antisense morpholino oligonucleotide-mediated knockdown of endogenous PRMT1 reduces proliferating epithelial stem cells (Matsuda & Shi, 2010). PRMT1 likely exerts its effect on intestinal stem cells by functioning as a TR coactivator to increase T3 signaling (Matsuda et al., 2009), although PRMT1 may also act as a coactivator for other transcription factors during stem cell development and/or proliferation or via methylation of non-histone proteins. Similarly, oncogene ectopic viral integration site 1 (EVI) and its variant myelodysplastic syndrome 1 (MDS)/EVI are highly induced by T3 at the climax of intestinal remodeling in Xenopus laevis and Xenopus tropicalis (Miller et al., 2013; Okada & Shi, 2018b). Knocking out the genes by targeting a common region with gene editing causes severe inhibition of tadpole growth and development during metamorphosis and results in partial lethality at metamorphic climax (Okada & Shi, 2018b). Importantly, the knockout tadpoles have reduced adult intestinal epithelial stem cell proliferation at the end of metamorphosis (for the few surviving animals) or during T3-induced metamorphosis (Okada & Shi, 2018b), revealing a novel function of EVI and/or MDS/EVI during vertebrate development.

A surprising finding among the T3-induced genes having an effect on intestinal stem cell development is Mad1, an antagonist of c-Myc in the Myc/Mad/Max network (Okada et al., 2017). Both Mad1 and c-Myc heterodimerize with Max and bind to the same target genes with opposing effect. While c-Myc is a well-known oncogene that activate target gene transcription and promote cell proliferation, Mad represses the expression of c-Myc target genes and is associated with quiescence or cell differentiation. In addition, c-Myc overexpression can induce cell death (Amati & Land, 1994; Dang, 1999; Koskinen & Alitalo, 1993; Kuchino, Asai, & Kitanaka, 1996; McMahon, 2014; Nieminen, Partanen, & Klefstrom, 2007; Packham & Cleveland, 1995; Pelengaris, Rudolph, & Littlewood, 2000; Shi et al., 1992; Thompson, 1998), while Mad is often anti-apoptotic (Amati & Land, 1994; Grandori, Cowley, James, & Eisenman, 2000; Luscher, 2012; McArthur et al., 1998). Consistent with these opposing roles, Mad1 and c-Myc are expressed in distinct epithelial cells during intestinal metamorphosis, with c-Myc expressed in the proliferating adult stem cells while Mad1 in the apoptotic larval epithelial cells (Fig. 4), implicating a surprising role of Mad1 in developmental cell death (Okada et al., 2017). Indeed, knocking out Mad1 inhibits/delays larval epithelial cell death during T3-induced intestinal metamorphosis but unexpectedly, the knockout tadpoles have increased adult epithelial stem cell proliferation during T3-induced metamorphosis (Okada et al., 2017). While the mechanism remains to be determined, one likely scenario is that Mad1 knockout inhibits/delays larval epithelial cell death, allowing more larval epithelial cells or giving larval epithelial cells, which otherwise would undergo T3-induced apoptosis, more time to undergo dedifferentiation into adult epithelial stem cells. Alternatively, Mad1 may be expressed at low levels, not detectable by in situ hybridization as shown in Fig. 4, in developing adult stem cells that express c-Myc. The removal of this low level of Mad1 in the knockout animals thus alters the balance of Mad-Myc, leading to increased stem cell proliferation during T3-induced metamorphosis.

Fig. 4.

Fig. 4

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Distinct expression patterns for the oncogene c-Myc and its antagonist Mad1 in the intestinal epithelium during metamorphosis. in situ hybridization analysis of Mad1 and c-Myc mRNAs was carried out on intestinal cross-sections of Xenopus laevis premetamorphic tadpoles (stage 54), metamorphosing tadpoles (stages 61/62 or climax), and post metamorphic froglets (stage 66). Panels a and b are higher magnification photos of the boxed region at stage 61/62 for Mad1 and c-Myc, respectively. Note that both Mad1 and c-Myc have little expression during premetamorphosis but are strongly activated at the climax (stages 61/62) with Mad expressed in the dying larval epithelial cells (arrowheads) while c-Myc expressed in the epithelial region close to the connective tissue (arrows). The dotted lines mark the approximate boundary between the epithelium (Ep) and the connective tissue (C). Scale bar, 50μm. Lu, lumen; Mu, muscle; Ty, typhlosole. Modified after Okada, M., Miller, T.C., Wen, L., & Shi, Y.B. (2017). A balance of Mad and Myc expression dictates larval cell apoptosis and adult stem cell development during Xenopus intestinal metamorphosis. Cell Death & Disease 8, e2787.

The involvement of Myc/Mad/Max network in both larval epithelial cell death and adult stem cell formation and/or proliferation is also consistent with recent RNA-seq analysis of genes regulated by T3 in the intestine of premetamorphic Xenopus tropicalis tadpoles after 1 day T3 treatment (Tanizaki, Shibata, Zhang, & Shi, 2020). T3 treatment of premetamorphic tadpoles at stage 54 is known to induce larval epithelial cell death after 2 days and formation and proliferation of adult intestinal stem cells after 3 days. Interestingly, gene ontology and biological pathway analyses of the T3-regulated genes revealed that the gene ontology terms and signaling pathways related to cell cycle regulation were highly enriched among the regulated genes after 1 day of T3 treatment, which was too short for T3 to induce any larval cell death or stem cell formation/proliferation in the tadpole intestine. By comparing the RNA-seq data of the wild type TRα knockout tadpole intestine, it was found that the endogenous TRα was important for the regulation of the cell cycle program. The intestine in premetamorphic tadpoles are made of predominantly larval epithelial cells, surrounded by thin layers of connective tissue and muscles (Fig. 2). Furthermore, most cell death and proliferation during metamorphosis occur in the epithelium (Fig. 2) (Okada, Wen, et al., 2015). The observed activation of the cell cycle program after 1 day of T3 treatment presumably reflected the changes in gene expression within the larval epithelium. The findings from the RNA-seq analyses thus suggest a novel model for T3 function during intestinal remodeling. That is, T3, mainly via TRα, which is expressed at a much higher level compared to TRβ in premetamorphic tadpole intestine (Wang et al., 2008), induces the cell cycle program in the larval epithelial cells. This, in turn, may facilitate the differentiated larval intestinal epithelial cells to initiate cellular changes toward two alternative fates: death via apoptosis or dedifferentiation to become adult stem cells. Clearly, it would be interesting to test this model.

6. Conservations between Xenopus intestinal metamorphosis and mammalian intestinal maturation

As mentioned above, mouse intestinal maturation occurs within the first 3 weeks or so after birth when plasma T3 concentration peaks, just like during amphibian metamorphosis. In addition, T3 or TR deficiency leads to adult intestinal defects in mouse, including reduced proliferating crypt cells (Flamant et al., 2002; Kress et al., 2009; Plateroti et al., 1999, 2001, 2006). Furthermore, human patients with TRα mutations have constipations, implicating intestinal defects, unlike patients with TRβ mutations (Bochukova et al., 2012; Moran & Chatterjee, 2015; Refetoff, Weiss, & Usala, 1993; van Mullem et al., 2012), supporting a specific role of TRα in the intestine. Consistently, a knockin mutation in the mouse TRα gene mimicking human TRα mutant patients also results in constipations in the adult mice (Bao et al., 2019). More importantly, analyses of the adult intestine in the knockin mutant have revealed drastically reduced cell proliferation in the crypts and altered epithelial cell differentiation (Bao et al., 2019), although only minor effect on the morphology of the villus-crypt axis due to compensatory reduction in epithelial cell death on the villus (Bao et al., 2019, 2020). All these point to a role of T3 and TR in intestinal maturation and adult stem cell function.

Interestingly, PRMT1, a gene that is induced by T3 and important for intestinal stem cell formation/proliferation (see above), is also upregulated during intestinal maturation in mouse and zebrafish when T3 levels are high (Matsuda & Shi, 2010). There is little or no PRMT1 mRNA in the zebrafish larval intestine or mouse neonatal intestine. During intestinal maturation when T3 levels peaks (Brown, 1997; Friedrichsen et al., 2003), PRMT1 is upregulated specifically in the bottom of the developing epithelial fold in zebrafish intestine and the developing crypt in mouse intestine, suggesting that conserved roles of T3 and PRMT1 for the formation and/or proliferation of the adult stem cells in vertebrates. Further support for the conservation in adult intestinal stem cell development came from genetic studies on B lymphocyte-induced maturation protein 1 (Blimp1) (Harper et al., 2011; Muncan et al., 2011). Blimp1, a transcriptional repressor, is strongly and uniformly expressed in the intestinal epithelium up to newborn mice before crypts are formed. With rising T3 concentration after birth, the crypt begins to form within the inter-villus pockets of the intestine where Blimp1 expression is reduced. As the intestine develops further, Blimp1 expression is repressed in all crypt cells and eventually the rest of the epithelium in the adult mice, likely due to the gradual replacement of the neonatal epithelium by the newly differentiated cells originated from the crypts. These findings suggest that Blimp1 repression is an early event in the epithelial transformation to form the adult stem cells. The distinct expression profiles of PRMT1 and Blimp1 in the neonatal intestine compared to the adult intestinal stem cells in the crypts suggest that like anuran intestinal metamorphosis, mouse intestinal maturation involves de novo formation of adult stem cells in a conserved process regulated by T3.

7. Conclusion

The ability to easily manipulate amphibian metamorphosis and the recent advancement in molecular and genetic studies in Xenopus have made this process highly valuable model for studying postembryonic organ development in vertebrates (Bilesimo et al., 2011; Brown & Cai, 2007; Buchholz et al., 2006; Buchholz & Shi, 2018; Grimaldi et al., 2013; Matsuura et al., 2012; Shi, 2013; Shi et al., 2012). Important insights have been gained from studying intestinal metamorphosis in Xenopus laevis and Xenopus tropicalis. Among them are the discovery that adult intestinal epithelial stem cells are formed de novo via T3-induced dedifferentiation of some larval epithelial cells and that this process resembles postembryonic intestinal maturation in mouse. Furthermore, a number of novel genes important for adult stem cell development/proliferation have been discovered from the identification and functional analyses of some of T3 target genes during intestinal remodeling. Given the important role of T3 in intestinal maturation and adult intestinal physiology, these novel adult stem cell genes will likely have conserved roles in mammalian intestinal maturation and function. The availability of many T3-induced genes in the developing intestinal stem cells, i.e., candidate stem cell genes, and the recent advancements in genetic analysis in Xenopus (Blitz et al., 2013; Lei et al., 2012, 2013; Nakade et al., 2014; Nakayama et al., 2013; Shi et al., 2015; Wang et al., 2015; Young et al., 2011) will ensure intestinal metamorphosis to be as a highly valuable model for further studying adult stem cell development in vertebrates.

Acknowledgment

This work was supported by the intramural Research Program of NICHD, NIH.

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