Thyrocyte-specific Dicer1 deficiency alters thyroid follicular organization and prevents goiter development.

MicroRNAs (miRNAs) are important regulators of posttranscriptional gene expression and involved in embryonic development, regulation of cell differentiation, and growth. Dicer1 is a key enzyme in the maturation process of functional miRNAs. However, miRNA-mediated regulation of normal thyroid function and growth is largely unknown. To understand the role of miRNAs in the thyroid, we generated constitutive and tamoxifen-inducible, thyrocyte-specific Dicer1 knockout mice. The mice with perinatal Dicer1 deletion (cTgDcrKO) showed impaired follicular organization, increased fibrosis, and accumulation of adipocytes in the thyroid. Similar histological changes were observed in tamoxifen-induced adult Dicer1-deficient mice (iTgDcrKO). The thyroid phenotype in both knockout (KO) lines was associated with significantly down-regulated mRNA expression of thyroid transcription factor 1 (Ttf-1/Nkx2-1), thyroid peroxidase, and thyroglobulin (Tg) and up-regulated expression of genes involved in Tgf-β signaling. Furthermore, in cTgDcrKO mice, which developed mild hypothyroidism, the protein expression of Nkx2-1, thyroglobulin, Paired box 8, and TSH receptor were clearly down-regulated compared with controls. Despite similar down-regulation of Dicer1 in cTgDcrKO and iTgDcrKO compared with controls, Dicer1 deletion in adult mice thyrocytes did not lead to acute hypothyroidism. No significant differences in thyroid weights between cTgDcrKO, iTgDcrKO, and controls were observed. However, a goitrogenic diet induced a 4-fold increase in thyroid weight in control animals, whereas it had no effect on iTgDcrKO thyroids. In summary, Dicer1 deficiency in thyrocytes is associated with intrathyroid fibrosis, adipogenesis, and enhanced expression of Tgf-β signaling genes. Furthermore, our data indicate that Dicer1 is required for thyroid follicular organization, thyrocyte differentiation, and goiter development.

Pubmed ID: 25594698 RIS Download