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

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, TR alpha is highly expressed during both premetamorphosis and metamorphosis while TR beta 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 TR alpha and TR beta has different effects on tadpole development. In particularly, homozygous TR beta-knockout tadpoles become tailed frogs well after sibling wild type ones complete metamorphosis. Most noticeably, in TRA-knockout tadpoles, an apparently normal notochord is present when the notochord in wild-type and TR alpha-knockout tadpoles disappears. Here, we have investigated how tail notochord resorption is regulated by TR. We show that TR beta is selectively very highly expressed in the notochord compared to TR alpha. 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 TR beta expression in the notochord specifically upregulate these MMPs, which in turn degrades the ECM, leading to the collapse of the notochord and its subsequent resorption during metamorphosis.