As a first step in the production of thyroid hormones, thyroid epithelial cells are devoted to the synthesis and secretion of thyroglobulin (Tg) into the follicle lumen. For this purpose, Tg is packaged into intracellular secretory granules whose exocytosis at the apical plasma membrane is regulated by thyrotropin. There is also reason to believe that these cells exhibit constitutive exocytotic discharge of other secretory vesicles, using specific pathways that direct newlysynthesized secretory proteins to the apical or basolateral surfaces. Thus, if thyroid cells could be grown in culture in a way which preserves their polar physiologic function, and allows experimental access to both apical and basolateral surfaces, they could serve as an ideal system for which to explore secretory sorting. Recent advances in cell culture techniques suggest that this goal is now possible. The purpose of the present proposal is to identify the exocytotic routes in a polarized monolayer of cultured cells taken by different secretory protein species (or by different posttranslational forms of the same species). In addition, the polarized exocytotic delivery of selected plasma membrane proteins will be examined and compared with that of secreted proteins. This then, will represent the first experimental model which can resolve each of the apical, basolateral, regulated and constitutive secretory pathways in a single system. As such, it will have the capability to answer questions of generalized significance about the targeting of endogenous and exogenous (DNA-transfected) secretory proteins, that heretofore could not be asked. Moreover, by establishing the routing of these secretory pathways in thyroid follicular cells, aspects of basic thyroid physiology will be re-explored, to gain an insight into normal and pathological thyroid function.
| Ferris, Sean P; Jaber, Nikita S; Molinari, Maurizio et al. (2013) UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility in the endoplasmic reticulum. Mol Biol Cell 24:2597-608 |
| Gualeni, Benedetta; Rajpar, M Helen; Kellogg, Aaron et al. (2013) A novel transgenic mouse model of growth plate dysplasia reveals that decreased chondrocyte proliferation due to chronic ER stress is a key factor in reduced bone growth. Dis Model Mech 6:1414-25 |
| Peteiro-Gonzalez, D; Lee, J; Rodriguez-Fontan, J et al. (2010) New insights into thyroglobulin pathophysiology revealed by the study of a family with congenital goiter. J Clin Endocrinol Metab 95:3522-6 |
| Lee, Jaemin; Wang, Xiaofan; Di Jeso, Bruno et al. (2009) The cholinesterase-like domain, essential in thyroglobulin trafficking for thyroid hormone synthesis, is required for protein dimerization. J Biol Chem 284:12752-61 |
