Sterner ZR and Buchholz DR (2022), Glucocorticoid receptor mediates corticosterone...

XB-ART-58627

Gen Comp Endocrinol 2022 Jan 01;315:113942. doi: 10.1016/j.ygcen.2021.113942.

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Glucocorticoid receptor mediates corticosterone-thyroid hormone synergy essential for metamorphosis in Xenopus tropicalis tadpoles.

Sterner ZR , Buchholz DR .

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In all vertebrates, thyroid hormone (TH) is critical for normal growth and development. In amphibians, corticosterone (CORT) has no action to advance development by itself but can accelerate development induced by TH. CORT accomplishes this acceleration by increasing tissue sensitivity and responsivity to TH. However, the receptor through which CORT acts to affect TH signaling is not known. To examine the role of the glucocorticoid receptor (GR), GR knockout tadpoles and wild-type tadpoles treated with the GR antagonist, RU486, were exposed to exogenous TH and/or CORT then assayed for gene expression and morphology. We found that levels of the response genes klf9 and thrb induced by TH and associated changes in morphology were decreased in GR knockout tadpoles compared to wild-type tadpoles, suggesting that GR signaling contributes to tissue responsivity to TH. To directly examine the role of GR in TH signaling, we co-treated tadpoles with TH and CORT and found that the TH response gene, thrb, was induced significantly beyond the level induced by TH alone in wild-type tadpoles but not in GR knockout tadpoles or wild-type tadpoles treated with RU486. Similarly, tail and gill resorption was greater in tadpoles treated with CORT plus TH compared to TH alone in wild-type tadpoles but not in tadpoles with impaired GR signaling. Surprisingly, even though GR knockout tadpoles die at metamorphosis, treatment with TH alone enabled their survival. These results demonstrate that signaling through GR is responsible for enhancing TH signaling and is essential for the completion of metamorphosis.

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Species referenced: Xenopus tropicalis
Genes referenced: klf9 rpl8 thrb
GO keywords: glucocorticoid receptor activity [+]

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	Fig. 1. GRKO tadpoles have reduced TH tissue responsivity and survive metamorphosis if provided T3. T3 induction levels of (A) klf9 and (B) thrb expression in tail are reduced in GRKO tadpoles. WT and GRKO tadpoles at NF 54 were treated for 24 h, and then tails were harvested to perform gene expression analysis, n = 5. (C) Exogenous T3 increased the rate of metamorphosis in GRKO and allowed them to survive through tail resorption. WT and GRKO tadpoles at NF 60 were treated daily with 10 nM and 20 nM T3, and days to NF 62, 64, and 66 were recorded. n = 6. Letters represent significance groups among all treatments within a panel, and circles represent significance groups within each treatment. Error bars represent standard error of the mean. WT = wild-type, GRKO = glucocorticoid receptor knockout, T3 = active form of TH.
	Fig. 2. GRKO tadpoles exhibit lack of CORT/TH synergy for thrb expression in the tail. WT and GRKO tadpoles at NF 54 were treated for 24 h with vehicle, 100 nM CORT, 2 nM T3, and 100 nM CORT plus 2 nM T3, and then gene expression was examined for (A) klf9 in tail, (B) thrb in tail, (C) klf9 in liver, and (D) thrb in liver. White portions of treatment bars for hormone co-treatments significantly higher than in T3 alone represent expression above additive response estimated from T3 and CORT responses singly. Black arrow indicates a synergistic response, defined as greater than one standard deviation above the estimated additive portion of the response. Error bars represent standard deviation (SD). Letters represent significance groups among all treatments within each panel. n = 12, WT = wild-type, GRKO = glucocorticoid receptor knockout, Veh = vehicle (ethanol treatment), CORT = corticosterone, T3 = active form of TH.
	Fig. 3. Wild-type tadpoles treated with RU486 exhibit lack of CORT/TH synergy for thrb expression in tail. WT and RU486-treated tadpoles at NF 54 were treated with vehicle, 100 nM CORT, 2 nM T3, and 100 nM CORT plus 2 nM T3, and then gene expression was examined for (A) klf9 in tail, (B) thrb in tail, (C) klf9 in liver, and (D) thrb in liver. White portions of treatment bars for hormone co-treatments significantly higher than in T3 alone represent expression above additive response estimated from T3 and CORT responses singly. Black arrow indicates a synergistic response, defined as greater than one standard deviation above the estimated additive portion of the response. Error bars represent standard deviation (SD). Letters represent significance groups among all treatments within each panel. n = 8, WT = wild-type, GRKO = glucocorticoid receptor knockout, Veh = vehicle (ethanol treatment), CORT = corticosterone, T3 = active form of TH.
	Fig. 4. Exemplar images of WT and GRKO tadpoles treated with or without T3 and/or CORT. Representative images of WT and GRKO tadpoles treated for 6 days with vehicle, 2 nM T3, and 100 nM CORT plus 2 nM T3 are shown. Note the stronger effect of T3 + CORT compared to T3 alone in tail and gill in wild-type (WT) and not GRKO tadpoles. n = 5, Veh = vehicle (ethanol treatment), T3 = active form of TH.
	Fig. 5. GRKO tadpoles exhibit lack of CORT/TH synergy for tail and gill resorption. WT and GRKO were measured before and after treatment for 6 days with vehicle, 100 nM CORT, 2 nM T3, and 100 nM CORT plus 2 nM T3. Bars represent average total change from Day 0 to Day 6 in (A) NF stage, (B) tail length, (C) hindlimb length, and (D) gill width. Letters represent significance groups among all treatments within each panel. Error bars represent standard deviation. n = 5, WT = wild-type, GRKO = glucocorticoid receptor knockout, Veh = vehicle (ethanol treatment), CORT = corticosterone, T3 = active form of TH.
	Fig. 6. Exemplar images of WT and RU486-treated tadpoles treated with or without T3 and/or CORT. Representative images of WT and RU486-treated tadpoles treated for 6 days with vehicle, 2 nM T3, and 100 nM CORT plus 2 nM T3 are shown. Note the stronger effect of T3 + CORT compared to T3 alone in tail and gill in wild-type (WT) and not RU486-treated tadpoles. n = 5, Veh = vehicle (ethanol treatment), RU486 = GR antagonist, T3 = active form of TH.
	Fig. 7. WT tadpoles treated with RU486 exhibit lack of CORT/TH synergy for tail and gill resorption. WT and RU486-treated tadpoles were measured before and after treatment for 6 days with vehicle, 100 nM CORT, 2 nM T3, and 100 nM CORT plus 2 nM T3. Bars represent average total change from Day 0 to Day 6 in (A) NF stage, (B) tail length, (C) hindlimb length, and (D) gill width. Letters represent significance groups among all treatments within each panel. Error bars represent standard deviation. n = 5, WT = wild-type, RU486 = GR antagonist, CORT = corticosterone, T3 = active form of TH.