Partial thyrocyte-specific Gαs deficiency leads to rapid-onset hypothyroidism, hyperplasia, and papillary thyroid carcinoma-like lesions in mice

Abstract

Thyroid function is controlled by thyroid-stimulating hormone (TSH), which binds to itsG protein-coupled receptor [thyroid-stimulating hormone receptor (TSHR)] on thyrocytes. TSHR can potentially couple to all G protein families, but it mainly activates the Gs- and Gq/11-mediated signaling cascades. To date, there is a knowledge gap concerning the role of the individual G protein cascades in thyroid pathophysiology. Here, we demonstrate that the thyrocyte-specific deletion of Gs protein α subunit (Gαs) in adult mice [tamoxifen-inducible Gs protein a subunit deficient (iTGαsKO) mice] rapidly impairs thyrocyte function and leads to hypothyroidism. Consequently, iTGαsKO mice show reduced food intake and activity. However, body weight and the amount of white adipose tissue were decreased only in male iTGαsKO mice. Unexpectedly, hyperplastic follicles and papillary thyroid cancer-like tumor lesionswith increased proliferation and slightly increased phospho-ERK1/2 stainingwere found in iTGαsK Omice at an older age. The setumors developed from nonrecombined thyrocytes still expressing Gαs in the presence of highly elevated serum TSH. In summary, we report that partial thyrocyte-specific Gαs deletion leads to hypothyroidism but also to tumor development in thyrocytes with remaining Gαs expression. Thus, these mice are a novel model to elucidate the pathophysiological consequences of hypothyroidism and TSHR/Gs/cAMP-mediated tumorigenesis.