Dev Biol 2025 Nov 12; doi: 10.1016/j.ydbio.2025.11.006.

Direct activation of folate receptor 4 by thyroid hormone suggests its role in the development of adult intestinal epithelium during Xenopus laevis metamorphosis.

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Amphibian metamorphosis is tightly regulated by thyroid hormone (TH). During this process, most larval epithelial cells in the Xenopus laevis intestine undergo apoptosis, whereas a small population dedifferentiates into adult epithelial stem cells. They subsequently proliferate and differentiate to form a trough-crest epithelial architecture similar to the mammalian crypt-villus axis. We have previously identified a number of TH-responsive genes likely involved in this intestinal remodeling. Here, we focus on one such gene, folate receptor 4 (folr4). We examined the spatiotemporal expression of folr4.L by using quantitative RT-PCR and in situ hybridization chain reaction (HCR) and found that folr4.L expression is highly upregulated during both natural and TH-induced metamorphosis. Interestingly, in the epithelium at the climax of metamorphosis, folr4.L is specifically expressed in the proliferating and/or differentiating adult epithelial cells located adjacent to proliferating adult stem cells, which express intestinal stem cell marker leucine-rich repeat-containing G protein-coupled 5 (lgr5). Moreover, we identified a TH response element (TRE) in the folr4.L promoter that binds to the heterodimer of TH receptor (TR) and 9-cis retinoic acid receptor (RXR) in vitro and mediates T3-dependent transcriptional activation in vivo. Phylogenetic analysis suggested that X. laevis Folr4.L may be more closely related to riboflavin binding protein (Rfbp) than mammalian FOLR4. These findings suggest that TH-induced Folr4.L might be involved in the development of adult intestinal epithelium.

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