TSH Compensates Thyroid-Specific IGF-I Receptor Knockout and Causes Papillary Thyroid Hyperplasia

Abstract

Although TSH stimulates all aspects of thyroid physiology IGF-I signaling through a tyrosine kinase-containing transmembrane receptor exhibits a permissive impact on TSH action. To better understand the importance of the IGF-I receptor in the thyroid in vivo, we inactivated the Igf1r with a Tg promoter-driven Cre-lox system in mice. We studied male and female mice with thyroidal wild-type, Igf1r(+/-), and Igf1r(-/-) genotypes. Targeted Igf1r inactivation did transiently reduce thyroid hormone levels and significantly increased TSH levels in both heterozygous and homozygous mice without affecting thyroid weight. Histological analysis of thyroid tissue with Igf1r inactivation revealed hyperplasia and heterogeneous follicle structure. From 4 months of age, we detected papillary thyroid architecture in heterozygous and homozygous mice. We also noted increased body weight of male mice with a homozygous thyroidal null mutation in the Igf1r locus, compared with wild-type mice, respectively. A decrease of mRNA and protein for thyroid peroxidase and increased mRNA and protein for IGF-II receptor but no significant mRNA changes for the insulin receptor, the TSH receptor, and the sodium-iodide-symporter in both Igf1r(+/-) and Igf1r(-/-) mice were detected. Our results suggest that the strong increase of TSH benefits papillary thyroid hyperplasia and completely compensates the loss of IGF-I receptor signaling at the level of thyroid hormones without significant increase in thyroid weight. This could indicate that the IGF-I receptor signaling is less essential for thyroid hormone synthesis but maintains homeostasis and normal thyroid morphogenesis.

Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation

“…Both mutant mouse lines were fertile and showed apparently normal phenotypes, although we noticed significant overweig in Nkx2-1-Cre; Igf1r fl/fl mice after puberty when compared with Igf1r fl/fl normal littermates (data not shown), condition that could be due to the lack of Igf1r in thyroid cells as a consequence of Cre expression in these cells driven by the Nkx2-1 promoter, as previously reported [40, 43]. Accordingly, mice with a homozygous thyroidal null mutation in the Igf1r locus also showed increased body weight [44]. A PCR-based analysis of genomic DNA, obtained from a variety of tissues to determine the Cre-mediated deletion in the Igf1r gene (S1 Fig, panels D-G), demonstrated that it specifically occurs in the adult lungs of both double transgenic mutants, but with much higher efficiency in Nkx2-1-Cre; Igf1r fl/fl (Fig 2A) than in Scgb1a1-Cre; Igf1r fl/fl mice (S1 Fig, panels F-G).…”

“…Accordingly, lack of Igf1 and Igf1r was reported to promote cell proliferation and/or to alter epithelial differentiation not only in the lung [25, 26, 28, 29, 31], but also in the prostate, thyroid gland, liver and nervous system[31, 44, 72, 73]. Furthermore, limited activity of Igf1r accelerates tumorigenesis and promotes more aggressive phenotypes in prostate and breast cancer in mice [72, 74].…”

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

“…It is unclear why different IGF-Idependency of IRS-2 translocation was shown in subcellular fractionation of HEK293 cells and FRTL-5 cells (Figs 4d and 5d). Thyroid epithelial cells synergistically proliferate in response to IGF-I and TSH in vitro [43][44][45] , which is thought to be important for thyroid morphogenesis and thyroid hormone homeostasis 46 . We previously reported that TSH or other cAMP-generating reagents enhance IGF-I-induced cell proliferation in thyroid FRTL-5 cells 44 .…”

Thyroid Regulatory Factors

“…In dog and human thyroid primary cultures, the presence of insulin receptors strictly depends on TSH and also mediates a comitogenic action of physiologic insulin concentrations, suggesting that thyroid might be a more specific target of insulin than generally considered. 22 Whether that could explain the observation that elevated TSH compensates thyroid-specific IGF-1 receptor knockout in mice 23 remains to be explored.…”