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Biochem Biophys Res Commun
2021 Aug 06;565:91-96. doi: 10.1016/j.bbrc.2021.05.082.
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TGF-β1 signaling is essential for tissue regeneration in the Xenopus tadpoletail.
Nakamura M
,
Yoshida H
,
Moriyama Y
,
Kawakita I
,
Wlizla M
,
Takebayashi-Suzuki K
,
Horb ME
,
Suzuki A
.
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Amphibians such as Xenopus tropicalis exhibit a remarkable capacity for tissue regeneration after traumatic injury. Although transforming growth factor-β (TGF-β) receptor signaling is known to be essential for tissue regeneration in fish and amphibians, the role of TGF-β ligands in this process is not well understood. Here, we show that inhibition of TGF-β1 function prevents tail regeneration in Xenopus tropicalis tadpoles. We found that expression of tgfb1 is present before tail amputation and is sustained throughout the regeneration process. CRISPR-mediated knock-out (KO) of tgfb1 retards tail regeneration; the phenotype of tgfb1 KO tadpoles can be rescued by injection of tgfb1 mRNA. Cell proliferation, a critical event for the success of tissue regeneration, is downregulated in tgfb1 KO tadpoles. In addition, tgfb1 KO reduces the expression of phosphorylated Smad2/3 (pSmad2/3) which is important for TGF-β signal-mediated cell proliferation. Collectively, our results show that TGF-β1 regulates cell proliferation through the activation of Smad2/3. We therefore propose that TGF-β1 plays a critical role in TGF-β receptor-dependent tadpoletail regeneration in Xenopus.
Fig. 1. Expression of tgfb1 in X. tropicalis tadpoles before and after tail amputation. Lateral views of uncut tadpole tails and amputated tails at 0, 0.25, 0.5, 1, 2, 4, 6, 12, 24, 48 and 72 h post amputation (hpa) after whole-mount in situ hybridization using tgfb1 antisense and sense RNA probes. Black arrowheads show amputation sites. Scale bar, 200 μm.
Fig. 2. TGF-β1 is required for Xenopus tail regeneration. (A) Schematic drawing of sgRNA target sites (sg 1, sg 2 and sg 3) in the tgfb1 locus. Grey boxes, untranslated region; green boxes, coding region; arrows, sgRNA target sites; bars, intron regions. (B) Delayed tail regeneration in tgfb1 KO tadpoles. The extent of tail regeneration was classified at 72 hpa as normal tail regeneration, weakly delayed tail regeneration, and severely delayed tail regeneration. (C) The phenotypes of tyrosinase KO (control) and tgfb1 KO tadpoles (sg 1 + 2 + 3) at 72 hpa. Black arrowheads show amputation sites. Scale bar, 200 μm.
Fig. 3. TGF-β1 regulates tissue differentiation and cell proliferation. (A) Lateral views of WISH performed with sox2 (spinal cord), myod1 (muscle) and shh (notochord) antisense RNA probes at 72 hpa. Scale bar, 200 μm. (B) Whole-mount immunostaining of phosphorylated Histone H3 (pH3) at 48 hpa. Scale bar, 100 μm. (C) Quantification of mitotic cells in the regenerating tail. The number of pH3 positive cells in tgfb1 KO and SB-505124-treated tadpoles was normalized against tyrosinase KO and DMSO-treated control tadpoles, respectively. Black and white arrowheads indicate amputation sites. ∗∗∗P < 0.001.
Fig. 4. TGF-β1 regulates the activation of Smad2/3. (A) Whole-mount immunostaining of phosphorylated Smad2/3 (pSmad2/3) at 6 hpa. Scale bar, 100 μm. (B) Quantitative fluorescence intensities of pSmad2/3 immunostaining in regenerating tails. The vertical axis indicates the average fluorescence intensity in regenerating tails of tgfb1 KO tadpoles normalized against tyrosinase KO control tadpoles. White arrowheads indicate amputation sites. White arrows indicate the localization of fluorescence signals in the regenerating tail tip. ∗P < 0.05.
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