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Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax

BACKGROUND: Animal regeneration is the natural process of replacing or restoring damaged or missing cells, tissues, organs, and even entire body to full function. Studies in mammals have revealed that many organs lose regenerative ability soon after birth when thyroid hormone (T3) level is high. Thi...

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Autores principales: Wang, Shouhong, Shibata, Yuki, Fu, Liezhen, Tanizaki, Yuta, Luu, Nga, Bao, Lingyu, Peng, Zhaoyi, Shi, Yun-Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9948486/
https://www.ncbi.nlm.nih.gov/pubmed/36823612
http://dx.doi.org/10.1186/s13578-023-00989-6
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author Wang, Shouhong
Shibata, Yuki
Fu, Liezhen
Tanizaki, Yuta
Luu, Nga
Bao, Lingyu
Peng, Zhaoyi
Shi, Yun-Bo
author_facet Wang, Shouhong
Shibata, Yuki
Fu, Liezhen
Tanizaki, Yuta
Luu, Nga
Bao, Lingyu
Peng, Zhaoyi
Shi, Yun-Bo
author_sort Wang, Shouhong
collection PubMed
description BACKGROUND: Animal regeneration is the natural process of replacing or restoring damaged or missing cells, tissues, organs, and even entire body to full function. Studies in mammals have revealed that many organs lose regenerative ability soon after birth when thyroid hormone (T3) level is high. This suggests that T3 play an important role in organ regeneration. Intriguingly, plasma T3 level peaks during amphibian metamorphosis, which is very similar to postembryonic development in humans. In addition, many organs, such as heart and tail, also lose their regenerative ability during metamorphosis. These make frogs as a good model to address how the organs gradually lose their regenerative ability during development and what roles T3 may play in this. Early tail regeneration studies have been done mainly in the tetraploid Xenopus laevis (X. laevis), which is difficult for gene knockout studies. Here we use the highly related but diploid anuran X. tropicalis to investigate the role of T3 signaling in tail regeneration with gene knockout approaches. RESULTS: We discovered that X. tropicalis tadpoles could regenerate their tail from premetamorphic stages up to the climax stage 59 then lose regenerative capacity as tail resorption begins, just like what observed for X. laevis. To test the hypothesis that T3-induced metamorphic program inhibits tail regeneration, we used TR double knockout (TRDKO) tadpoles lacking both TRα and TRβ, the only two receptor genes in vertebrates, for tail regeneration studies. Our results showed that TRs were not necessary for tail regeneration at all stages. However, unlike wild type tadpoles, TRDKO tadpoles retained regenerative capacity at the climax stages 60/61, likely in part by increasing apoptosis at the early regenerative period and enhancing subsequent cell proliferation. In addition, TRDKO animals had higher levels of amputation-induced expression of many genes implicated to be important for tail regeneration, compared to the non-regenerative wild type tadpoles at stage 61. Finally, the high level of apoptosis in the remaining uncut portion of the tail as wild type tadpoles undergo tail resorption after stage 61 appeared to also contribute to the loss of regenerative ability. CONCLUSIONS: Our findings for the first time revealed an evolutionary conservation in the loss of tail regeneration capacity at metamorphic climax between X. laevis and X. tropicalis. Our studies with molecular and genetic approaches demonstrated that TR-mediated, T3-induced gene regulation program is responsible not only for tail resorption but also for the loss of tail regeneration capacity. Further studies by using the model should uncover how T3 modulates the regenerative outcome and offer potential new avenues for regenerative medicines toward human patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-00989-6.
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spelling pubmed-99484862023-02-24 Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax Wang, Shouhong Shibata, Yuki Fu, Liezhen Tanizaki, Yuta Luu, Nga Bao, Lingyu Peng, Zhaoyi Shi, Yun-Bo Cell Biosci Research BACKGROUND: Animal regeneration is the natural process of replacing or restoring damaged or missing cells, tissues, organs, and even entire body to full function. Studies in mammals have revealed that many organs lose regenerative ability soon after birth when thyroid hormone (T3) level is high. This suggests that T3 play an important role in organ regeneration. Intriguingly, plasma T3 level peaks during amphibian metamorphosis, which is very similar to postembryonic development in humans. In addition, many organs, such as heart and tail, also lose their regenerative ability during metamorphosis. These make frogs as a good model to address how the organs gradually lose their regenerative ability during development and what roles T3 may play in this. Early tail regeneration studies have been done mainly in the tetraploid Xenopus laevis (X. laevis), which is difficult for gene knockout studies. Here we use the highly related but diploid anuran X. tropicalis to investigate the role of T3 signaling in tail regeneration with gene knockout approaches. RESULTS: We discovered that X. tropicalis tadpoles could regenerate their tail from premetamorphic stages up to the climax stage 59 then lose regenerative capacity as tail resorption begins, just like what observed for X. laevis. To test the hypothesis that T3-induced metamorphic program inhibits tail regeneration, we used TR double knockout (TRDKO) tadpoles lacking both TRα and TRβ, the only two receptor genes in vertebrates, for tail regeneration studies. Our results showed that TRs were not necessary for tail regeneration at all stages. However, unlike wild type tadpoles, TRDKO tadpoles retained regenerative capacity at the climax stages 60/61, likely in part by increasing apoptosis at the early regenerative period and enhancing subsequent cell proliferation. In addition, TRDKO animals had higher levels of amputation-induced expression of many genes implicated to be important for tail regeneration, compared to the non-regenerative wild type tadpoles at stage 61. Finally, the high level of apoptosis in the remaining uncut portion of the tail as wild type tadpoles undergo tail resorption after stage 61 appeared to also contribute to the loss of regenerative ability. CONCLUSIONS: Our findings for the first time revealed an evolutionary conservation in the loss of tail regeneration capacity at metamorphic climax between X. laevis and X. tropicalis. Our studies with molecular and genetic approaches demonstrated that TR-mediated, T3-induced gene regulation program is responsible not only for tail resorption but also for the loss of tail regeneration capacity. Further studies by using the model should uncover how T3 modulates the regenerative outcome and offer potential new avenues for regenerative medicines toward human patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-00989-6. BioMed Central 2023-02-23 /pmc/articles/PMC9948486/ /pubmed/36823612 http://dx.doi.org/10.1186/s13578-023-00989-6 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Wang, Shouhong
Shibata, Yuki
Fu, Liezhen
Tanizaki, Yuta
Luu, Nga
Bao, Lingyu
Peng, Zhaoyi
Shi, Yun-Bo
Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax
title Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax
title_full Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax
title_fullStr Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax
title_full_unstemmed Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax
title_short Thyroid hormone receptor knockout prevents the loss of Xenopus tail regeneration capacity at metamorphic climax
title_sort thyroid hormone receptor knockout prevents the loss of xenopus tail regeneration capacity at metamorphic climax
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9948486/
https://www.ncbi.nlm.nih.gov/pubmed/36823612
http://dx.doi.org/10.1186/s13578-023-00989-6
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