Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development
Jukka Kero, Kashan Ahmed, Nina Wettschureck, Sorin Tunaru, Tim Wintermantel, Erich Greiner, Günther Schütz, Stefan Offermanns
Jukka Kero, Kashan Ahmed, Nina Wettschureck, Sorin Tunaru, Tim Wintermantel, Erich Greiner, Günther Schütz, Stefan Offermanns
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Research Article Endocrinology

Thyrocyte-specific Gq/G11 deficiency impairs thyroid function and prevents goiter development

Abstract

The function of the adult thyroid is regulated by thyroid-stimulating hormone (TSH), which acts through a G protein–coupled receptor. Overactivation of the TSH receptor results in hyperthyroidism and goiter. The Gs-mediated stimulation of adenylyl cyclase–dependent cAMP formation has been regarded as the principal intracellular signaling mechanism mediating the action of TSH. Here we show that the Gq/G11-mediated signaling pathway plays an unexpected and essential role in the regulation of thyroid function. Mice lacking the α subunits of Gq and G11 specifically in thyroid epithelial cells showed severely reduced iodine organification and thyroid hormone secretion in response to TSH, and many developed hypothyroidism within months after birth. In addition, thyrocyte-specific Gαq/Gα11-deficient mice lacked the normal proliferative thyroid response to TSH or goitrogenic diet, indicating an essential role of this pathway in the adaptive growth of the thyroid gland. Our data suggest that Gq/G11 and their downstream effectors are promising targets to interfere with increased thyroid function and growth.

Authors

Jukka Kero, Kashan Ahmed, Nina Wettschureck, Sorin Tunaru, Tim Wintermantel, Erich Greiner, Günther Schütz, Stefan Offermanns

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Figure 1

Validation of thyrocyte-specific deletion of the genes encoding Gαq and Gα11.

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Validation of thyrocyte-specific deletion of the genes encoding Gαq and ...
(A) Gt(ROSA)26Sor Cre reporter animals (Cre reporter) carrying no Cre gene (top row) or carrying the Cre gene under the control of the thyroglobulin promoter (Tg-Cre; bottom) were analyzed at the indicated ages, and β-galactosidase staining was performed on whole-mount preparations as well as on sections (far right panels). trach., trachea; thyr., thyroid gland. Scale bars: 50 μm. Original magnification, ×12. (B) Western blot of thyroid gland lysates from 4-week-old wild-type (Gnaq+/+Gna11+/+), Gα11-deficient (Gnaqfl/flGna11–/–) and Tc-Gαq/Gα11–KO mice (Tg-Cre;Gnaqfl/flGna11–/–) probed with antibodies recognizing Gαq/Gα11 (Gαq/11) or ERK1/2. (C) cAMP levels in primary thyrocytes from wild-type and Tc-Gαq/Gα11–KO animals treated (+) or not (–) with 50 mU/ml TSH. Values are mean ± SEM of experiments performed in triplicate. (D) Effect of TSH (10 mU/ml), ATP (10 μM), and ionomycin (Iono; 1 μM) on [Ca2+]i in thyrocytes prepared from wild-type or Tc-Gαq/Gα11–KO animals. y axis values are measured 340/380-nm fluorescence ratios as an indicator of free [Ca2+]i.