KRÜPPEL-LIKE FACTOR 9 ENHANCES THYROID HORMONE RECEPTOR β AUTOINDUCTION IN TADPOLE BRAIN IN VIVO, INCREASING TISSUE SENSITIVITY TO THYROID HORMONE AND ACCELERATING METAMORPHOSIS
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1
University of Michigan, Molecular, Cellular and Developmental Biology, United States
Thyroid hormone (T3) receptor β (TRβ) is a direct T3 target gene that is strongly induced (autoinduced) during tadpole metamorphosis. TRβ autoinduction is thought to be critical for hormone action during metamorphosis. The transcription factor Krüppel-like factor 9 (KLF9) is the most rapidly responding T3 target gene thus far identified. Previously, we showed in the Xenopus cell line XTC-2 that KLF9 associates with the TRβ promoter to accelerate and enhance TRβ autoinduction. Here we show that KLF9 promotes TRβ autoinduction in tadpole brain in vivo. We used electroporation-mediated (EM) gene transfer to transfect plasmids into the brains of early prometamorphic tadpoles to express wild type or mutant forms of KLF9. Forced expression of KLF9 increased basal TRβ mRNA expression in euthyroid tadpoles, but had no effect in methimazole-treated, hypothyroid animals, suggesting that KLF9’s major action is to enhance liganded TR action. Similar to our findings in XTC-2 cells, forced expression of KLF9 accelerated TRβ autoinduction in tadpole brain in vivo and enhanced T3-dependent induction of the TR target gene TH/bZip. Consistent with our previous mutagenesis experiments conducted in XTC-2 cells, the actions of KLF9 in vivo did not depend on its DNA binding activity, but required the second transactivation domain ‘B’. Chronic, forced expression of KLF9 in tadpole brain accelerated metamorphosis, which we hypothesize is due to KLF9 increasing TRβ expression, and thereby enhancing tissue sensitivity to T3. In support of this hypothesis, we found that forced expression of TRβ in tadpole brain in vivo by EM gene transfer increased expression of TR target genes. We conclude that the immediate early transcription factor KLF9 participates in a transcriptional regulatory network to promote TRβ autoinduction in vivo, forming a positive feedback loop that sensitizes the cell to further hormonal stimulation owing to the production of more TRβ.
Acknowledgements
Supported by NIH grant R01 NS046690 and NSF grant IOS 0922583 to RJD
Keywords:
Autoinduction,
Hypothalamus,
metamorphosis,
nuclear receptor,
Thyroid hormone,
Xenopus
Conference:
ISAREN 2011: 7th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology, Ann Arbor, United States, 11 Jul - 13 Jul, 2011.
Presentation Type:
Poster
Topic:
Metamorphosis
Citation:
Hu
F,
Knoedler
J and
Denver
RJ
(2011). KRÜPPEL-LIKE FACTOR 9 ENHANCES THYROID HORMONE RECEPTOR β AUTOINDUCTION IN TADPOLE BRAIN IN VIVO, INCREASING TISSUE SENSITIVITY TO THYROID HORMONE AND ACCELERATING METAMORPHOSIS.
Front. Endocrinol.
Conference Abstract:
ISAREN 2011: 7th International Symposium on Amphibian and Reptilian Endocrinology and Neurobiology.
doi: 10.3389/conf.fendo.2011.03.00021
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Received:
18 Jul 2011;
Published Online:
09 Aug 2011.
*
Correspondence:
Prof. Robert J Denver, University of Michigan, Molecular, Cellular and Developmental Biology, Ann Arbor, United States, Rdenver@umich.edu