A unique role of thyroid hormone receptor β in regulating notochord resorption during Xenopus metamorphosis

Abstract

Tail resorption during anuran metamorphosis is perhaps the most dramatic tissue transformation that occurs during vertebrate development. Earlier studies in highly related anuran species Xenopus laevis and Xenopus tropicalis have shown that thyroid hormone (T3) receptor (TR) plays a necessary and sufficient role to mediate the causative effect of T3 on metamorphosis. Of the two known TR genes in vertebrates, TRα is highly expressed during both premetamorphosis and metamorphosis while TRβ expression is low in premetamorphic tadpoles but highly upregulated as a direct target gene of T3 during metamorphosis, suggesting potentially different functions during metamorphosis. Indeed, gene knockout studies have shown that knocking out TRα and TRβ has different effects on tadpole development. In particularly, homozygous TRβ knockout tadpoles become tailed frogs well after sibling wild type ones complete metamorphosis. Most noticeably, in TRβ-knockout tadpoles, an apparently normal notochord is present when the notochord in wildtype and TRα-knockout tadpoles disappears. Here, we have investigated how tail notochord resorption is regulated by TR. We show that TRβ is selectively very highly expressed in the notochord compared to TRα. We have also discovered differential regulation of several matrix metalloproteinases (MMPs), which are known to be upregulated by T3 and implicated to play a role in tissue resorption by degrading the extracellular matrix (ECM). In particular, MMP9-TH and MMP13 are extremely highly expressed in the notochord compared to the rest of the tail. In situ hybridization analyses show that these MMPs are expressed in the outer sheath cells and/or the connective tissue sheath surrounding the notochord. Our findings suggest that high levels of

Thyroid Hormone Receptor Is Essential for Larval Epithelial Apoptosis and Adult Epithelial Stem Cell Development but Not Adult Intestinal Morphogenesis during Xenopus tropicalis Metamorphosis

“…Of particular special interest is intestinal remodeling, which involves degeneration of the larval epithelium via apoptosis and de novo formation of the adult intestinal stem cells in an organ autonomous, T3-dependent manner, thus offering an opportunity to study how adult organ-specific stem cells are formed during vertebrate development. Recent knockout studies on individual Xenopus tropicalis TR genes, TR α or TR® , have revealed important gene- and organ-specific roles during Xenopus metamorphosis [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 43 , 46 ]. Interestingly, the two TR genes can compensate for each other to enable tadpoles to complete metamorphosis in the absence of either TR gene despite their distinct expression profiles during natural development.…”

“…With the development of gene-editing technologies and the advancement in genome annotation for diploid Xenopus tropicalis, we and others have generated single ( TR α or TR® ) or double TR knockout (TRDKO) animals that have not only supported the dual-function model, but also provided novel details on the role of TRs during Xenopus development [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Interestingly, single TR knockout tadpoles could complete metamorphosis with delayed developmental progression of different organs, suggesting compensation between TRα and TR® .…”

Stress hormones mediate developmental plasticity in vertebrates with complex life cycles

“…5 ) that promote transcription of genes that drive metamorphosis ( Kulkarni and Buchholz, 2014 ; Sachs and Buchholz, 2019 ). For example, CS can induce expression of TRs to increase cellular sensitivity to the hormone signal ( Bonett et al, 2010 ; Kikuyama et al, 1993 ; Niki et al, 1981 ; Suzuki and Kikuyama, 1983 ), especially TR beta which is necessary for proper completion of metamorphosis ( Nakajima et al, 2019 ; Shibata et al, 2020a , 2020b ). The actions of CSs were synergistic with low or subthreshold doses of TH, producing strong induction of TR expression ( Bonett et al, 2010 ).…”

Organ-Specific Requirements for Thyroid Hormone Receptor Ensure Temporal Coordination of Tissue-Specific Transformations and Completion ofXenopusMetamorphosis

“…With the advent of gene editing technologies that are applicable to amphibians, we and others have begun to investigate the role of endogenous TRs by using the diploid anuran X. tropicalis, which is highly related to X. laevis, especially with regard to metamorphosis (4,(28)(29)(30)(31)(32). Both TRa and TRb have been knocked out individually, and analyses of the single knockout animals have revealed interesting but distinct phenotypes (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). Knocking out TRa leads to derepression of T3-inducible genes in premetamorphic tadpoles and premature initiation of metamorphosis, as reflected by limb morphogenesis, and also decreased response to exogenous T3 and reduced rate of metamorphic progression during natural metamorphosis (33,34,(37)(38)(39)(40)(41).…”

“…However, it has no detectable effect on tail resorption with overall time from fertilization to the completion of metamorphosis similar between wild-type (WT) and knockout animals. However, knocking out TRb has little effect on premetamorphic development and limb metamorphosis but delays tail resorption (35,36,42). Interestingly, both TRa and TRb individual knockout animals can complete metamorphosis with no apparently morphological defects in the resulting froglets, raising an interesting question whether TR is required for metamorphosis, especially considering that inactivating both TRa and TRb does not impair mouse embryonic development (43,44).…”