The thyroid gland secretes thyroid hormones (THs) under regulation of thyroid stimulation hormone (TSH) and its receptor (TSHR). THs play a pivotal role in development, growth and metabolism. 

An increased secretion of THs causes hyperthyroidism, while a decrease leads to hypothyroidism. Together with thyroid tumors, these thyroid diseases affect more than 10 % of the population. Thus, better understanding of the molecular causes of thyroid diseases is crucial to improve treatment strategies. 

In this study, we generated genetically modified mouse models to understand the details of thyroid pathophysiology. First, a thyroglobulin promoter-driven, tamoxifen-inducible Cre-mouse line (iTgCre) was created to enable thyroid-specific gene deletions in a time-dependent manner using the Cre/loxP system. Thereafter, this technique was applied to delete the microRNA-processing enzyme Dicer1. Knocking out Dicer1 during development and adulthood revealed that Dicer1, and subsequently miRNAs, are crucial for the maintenance of thyrocyte differentiation and growth. Perinatal miRNA deficiency leads to slowly progressing hypothyroidism, while the deletion of miRNAs in adult mice does not cause acute hypothyroidism. 

Furthermore, to understand the development of hyperthyroidism, we generated a knock-in mouse model harboring a constitutively active TSHR mutation D633H. Interestingly, these TSHRD633H mice developed colloid goiter with euthyroidism, subclinical or overt hyperthyroidism depending on sex and age. 

In conclusion, we generated new disease models to understand molecular mechanisms in thyroid development, hypo- and hyperthyroidism. These findings revealed a novel role of miRNAs in thyroid growth, development and hypothyroidism. Furthermore, we demonstrated that TSHRD633H mutation causes transient hyperthyroidism and colloid goiter in mice.