Wen L , Shi YB .

Intramural NIH HHS, ZIA HD001901-22 Intramural NIH HHS, ZIA HD001901-23 Intramural NIH HHS

	Fig. 2. (A) Thyroid hormone (TH) receptor a (TRa) knockdown increases the expression of the TH-inducible gene Klf9 in premetamorphic tadpoles but reduces its induction by TH treatment of Xenopus tropicalis tadpoles. TRa was knocked down by injecting mRNAs encoding TALEN left (L) and right (R) arms into fertilized eggs. WT: no TALEN mRNA injection, TRa-R: TRa TALEN-R and control-L mRNAs injected, TRa-L: TRa TALEN-L arm and control-R mRNAs injected, and TRa-L+R:TRa TALEN-L and -R mRNAs injected. Premetamorphic tadpoles were treated with 10 nmol/L TH for 18 h and total RNA was isolated for reverse transcription–polymerase chain reaction (RT–PCR) analysis for the expression of Klf9. Note that its expression was higher in the TRa TALEN injected tadpoles in the absence of TH but lower in the presence of TH, respectively, when compared to the WT and control groups, suggesting that both the repression by unliganded TR and activation by TH-bound TR were reduced when TRa was knocked down. ** and * indicate significant difference between the TRa knockdown group compared to all three other groups (**P < 0.01, *P < 0.05). See (Wen & Shi 2015) for details. (B) TRa knockdown accelerates premetamorphic development. The animals were staged at the age of 20 days post-fertilization. Left panel: Representative animals with the area in dashed box magnified to show the hindlimb size and morphology. Note the more developed hindlimb for the TRa knockdown animal. Right panel shows the average developmental stages of the animals with different TALEN mRNA injections. Note that the TRa TALEN-injected group developed on average 3.5 stages more advanced compared to the other three groups. *Indicates significant difference between the TRa knockdown group compared to all three other groups (P < 0.05). See (Wen & Shi 2015) for details.
	Fig. 4. Schematics showing the dual effects of thyroid hormone (TH) receptor a (TRa) knockdown on premetamorphic development in Xenopus tropicalis. TRa knockdown has little effect on embryogenesis and the resulting tadpoles are normal by feeding stage (stage 45). Once feeding begins, the animals grow differently, with the knockdown ones growing faster, and thus larger when compared to wild type siblings at the same age (in days) (compared with the vertical axis values of the lines for the knockdown and wild type animals at any given position along the horizontal axis between stages 45 and 54). The knockdown animals also have faster development, reaching developmentally more advanced stages when compared to wild type siblings at the same age (in days). Thus, the knockdown animals reach stage 54, the onset of metamorphosis, at a younger age (see the horizontal axis locations for the upper end of the lines). Interestingly, when the animals at stage 54 are compared, the wild type ones are actually larger than the knockdown siblings even though the latter grow faster. This is because the wild type animals take longer to reach metamorphosis (stage 54). The extra growth time needed to reach stage 54 enables the wild type ones to catch up and surpass the knockdown ones in size. These results indicate that the effects of TR on growth and development are not dependent on each other (as otherwise, the size of the animals at stage 54 would be identical between the wild type and knockdown ones).
	Fig. 5. Transgenic expression of a dominant negative (dn) corepressor leads to premature metamorphosis in Xenopus laevis. (A) Schematic representation of dnN-CoR transgenic construct. The dnN-CoR was placed under the control of a heat shock-inducible promoter in a plasmid that also contained the c-crystallin promoter driving the expression of green fluorescent protein (GFP) for identification of transgenic tadpoles. (B) Experimental strategy. The transgenic and wild type animals are subjected to daily heat shock treatment at the onset of feeding, around stage 45, until they reach stage 54, the onset of metamorphosis when endogenous T3 and T4 becomes available (Leloup & Buscaglia 1977), which bind to TR to prevent the binding of dnN-coR to TR. (C) Transgenic tadpoles expressing the dnN-CoR initiate metamorphosis earlier than wild type siblings. Transgenic F1 generation tadpoles and wild type siblings at stage 46 were treated daily with heat shock to induce dnN-CoR expression in the transgenic but not wild type animals and their developmental stages were determined every 5 days for 30 days (note that at the end of the 30-day experiments, transgenic animals had initiated metamorphosis, i.e. passed stage 54, and thus the experiment was ended since the dnN-CoR would have no effect on TR when TH is present). The time (days) needed for the wild type animals to catch up the stage of the transgenic siblings at different time points of the heat shock treatment was calculated based on the staging by (Nieuwkoop & Faber 1956) and plotted here. See Fig. 1 and (Sato et al. 2007) for more details.

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