Abstract
Primary cilia are sensory organelles with a variety of receptors and channels on their membranes. Recently, primary cilia were proposed to be crucial sites for exocytosis and endocytosis of vesicles associated with endocytic control of various ciliary signaling pathways. Thyroglobulin (Tg) synthesis and Tg exocytosis/endocytosis are critical for the functions of thyroid follicular cells, where primary cilia are relatively well preserved. LRP2/megalin has been detected on the apical surface of absorptive epithelial cells, including thyrocytes. LRP2/megalin on thyrocytes serves as a Tg receptor and can mediate Tg endocytosis. In this study, we investigated the role of primary cilia in LRP2/megalin expression in thyroid gland stimulated with endogenous TSH using MMI-treated and Tg-Cre;Ift88flox/flox mice. LRP2/megalin expression in thyroid follicles was higher in MMI-treated mice than in untreated control mice. MMI-treated mice exhibited a significant increase in ciliogenesis in thyroid follicular cells relative to untreated controls. Furthermore, MMI-induced ciliogenesis accompanied increases in LRP2/megalin expression in thyroid follicular cells, in which LRP2/megalin was localized to the primary cilium. By contrast, in Tg-Cre;Ift88flox/flox mice, thyroid with defective primary cilia expressed markedly lower levels of LRP2/megalin. Serum Tg levels were elevated in MMI-treated mice and reduced in Tg-Cre;Ift88flox/flox mice. Taken together, these results indicate that defective ciliogenesis in murine thyroid follicular cells is associated with impaired LRP2/megalin expression and reduced serum Tg levels. Our results strongly suggest that primary cilia harbors LRP2/megalin, and are involved in TSH-mediated endocytosis of Tg in murine thyroid follicles.
Highlights
Thyroglobulin (Tg), the most abundant thyroid-specific protein synthesized by follicular cells, serves as the molecular template for the synthesis of thyroid hormones T4 and T3 at the thyrocyte–colloid interface
We demonstrated that Lrp2/megalin is localized in the primary cilium of thyroid follicular cells
Thyroid-specific cilium-deficient Tg-Cre;Ift88flox/flox mice exhibited a significant loss of Lrp2/megalin and a reduction in serum Tg despite the high TSH level
Summary
Thyroglobulin (Tg), the most abundant thyroid-specific protein synthesized by follicular cells (thyrocytes), serves as the molecular template for the synthesis of thyroid hormones T4 and T3 at the thyrocyte–colloid interface. A major regulatory step in thyroid hormone release in mammalian thyroid follicular cells is Tg endocytosis. This process requires micropinocytosis, which includes nonspecific fluid-phase pinocytosis and receptor-mediated endocytosis. Tg internalized by receptors is handled by post-endocytic pathways that sort Tg molecules to undergo lysosomal degradation, LRP2 and Primary Cilia in Thyroid transcytosis, or recycling. Clathrin-coated pits, caveolaedependent endocytosis, and low-density lipoprotein receptor protein 2 (LRP2, known as megalin) are involved in receptor-mediated endocytic pathways of Tg [1, 2]. LRP2/ megalin has been detected on the apical surface of thyrocytes; it serves as a Tg receptor and can mediate Tg endocytosis [1, 2]. Megalin knockout mice exhibit hypothyroidism, which is associated with reduced levels of serum Tg and free T4 (fT4) levels, and significantly elevated levels of serum TSH [3]
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