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

Background: Thyroid hormone (triiodothyronine [T3]) is essential for the development throughout vertebrates. Anuran metamorphosis mimics mammalian postembryonic development, a period around birth when plasma T3 level peaks and many organs/tissues mature into their adult forms. Compared with the uterus-enclosed mammalian embryos, tadpoles can be easily manipulated to study the roles of T3 and T3 receptors (TRs) in tissue remodeling and adult organ development. We and others have previously knocked out TR alpha or TR beta in the diploid anuran Xenopus tropicalis and reported distinct effects of the two receptor knockouts on metamorphosis. However, animals lacking either TR alpha or TR beta can complete metamorphosis and develop into reproductive adults. Methods: We have generated TR alpha and TR beta double knockout animals and carried out molecular and morphological analyses to determine if TR is required for Xenopus development. Results: We found that the TR double knockout tadpoles do not respond to T3, supporting the view that there are no other TR genes in X. tropicalis and that TR is essential for mediating the effects of T3 in vivo. Surprisingly, the double knockout tadpoles are able to initiate metamorphosis and accomplish many metamorphic changes, such as limb development. However, all double knockout tadpoles stall and eventually die at stage 61, the climax of metamorphosis, before tail resorption takes place. Analyses of the knockout tadpoles at stage 61 revealed various developmental abnormalities, including precocious ossification and extra vertebrae. Conclusions: Our data indicate that TRs are not required for the initiation of metamorphosis but is essential for the completion of metamorphosis. Furthermore, the differential effects of TR knockout on different organs/tissues suggest tissue-specific roles for TR to control temporal coordination and progression of metamorphosis in various organs.