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Embryonic exposure to excess thyroid hormone causes thyrotrope cell death
Ksenia N. Tonyushkina, … , Theresa Ortiz-Toro, Rolf O. Karlstrom
Ksenia N. Tonyushkina, … , Theresa Ortiz-Toro, Rolf O. Karlstrom
Published December 9, 2013
Citation Information: J Clin Invest. 2014;124(1):321-327. https://doi.org/10.1172/JCI70038.
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Research Article Article has an altmetric score of 13

Embryonic exposure to excess thyroid hormone causes thyrotrope cell death

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Abstract

Central congenital hypothyroidism (CCH) is more prevalent in children born to women with hyperthyroidism during pregnancy, suggesting a role for thyroid hormone (TH) in the development of central thyroid regulation. Using the zebrafish embryo as a model for thyroid axis development, we have characterized the ontogeny of negative feedback regulation of thyrotrope function and examined the effect of excess TH on thyrotrope development. We found that thyroid-stimulating hormone β subunit (tshb) and type 2 deiodinase (dio2) are coexpressed in zebrafish thyrotropes by 48 hours after fertilization and that TH-driven negative feedback regulation of tshb transcription appears in the thyroid axis by 96 hours after fertilization. Negative feedback regulation correlated with increased systemic TH levels from the developing thyroid follicles. We used a transgenic zebrafish that expresses GFP under the control of the tshb promoter to follow thyrotrope fates in vivo. Time-lapse imaging revealed that early exposure to elevated TH leads to thyrotrope cell death. Thyrotrope numbers slowly recovered following the removal of excess TH. These data demonstrate that transient TH exposure profoundly impacts the thyrotrope population during a critical period of pituitary development and may have long-term implications for the functional reserve of thyroid-stimulating hormone (TSH) production and the TSH set point later in life.

Authors

Ksenia N. Tonyushkina, Meng-Chieh Shen, Theresa Ortiz-Toro, Rolf O. Karlstrom

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Figure 3

Early embryonic exposure to high T4 levels leads to thyrotrope cell death.

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Early embryonic exposure to high T4 levels leads to thyrotrope cell deat...
(A) Ventral view of the zebrafish head in a 6-dpf Tg(tshb:EGFP) embryo showing GFP-labeled thyrotropes in the pituitary. (B–L) Single frames from a time-lapse movie (see Supplemental Video 1) of GFP-expressing thyrotropes (numbered) in a Tg(tshb:EGFP) embryo 4–14 hours after the application of 300 nM T4 48 hpf. (B) Eight GFP-expressing thyrotropes were present 4 hours after application of T4. (D and E) GFP-expressing thyrotropes began to disappear 6–7 hours after T4 application. (L) Only 3 cells remained 14 hours after application of T4. (M–O) Example of anti–activated caspase 3 labeling of 2 GFP-expressing thyrotropes (arrows) in a Tg(tshb:EGFP) embryo 10 hours after the application of 300 nM T4. Single focal plane images show GFP (M), caspase 3 (N), and merged channels (O). All panels show ventral views of the left anterior forebrain between the eyes. Scale bars: 25 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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