Classical cadherins and the thyroid. Studies on organ development and epithelial differentiation

Abstract

The cadherins are key regulators of tissue patterning and organ formation. E-cadherin is important for cell-cell adhesion and promotes epithelial morphogenesis and maintenance of the epithelial phenotype. Down-regulation of E-cadherin and upregulation of N-cadherin has been shown to be associated with the acquisition of a more migratory phenotype during normal embryogenesis as well as in tumor progression. The aim of this thesis was to study the classical cadherins in thyroid development and epithelial differentiation. Our findings show that co-stimulation of filter-cultured porcine thyrocytes with EGF and TGF- Ò1 induced changes not produced by either growth factor alone. The epithelial barrier function was abrogated, accompanied by down-regulation of the tight junction proteins and a massive upregulation of N-cadherin. Prolonged co-stimulation caused down-regulation of both E-cadherin and N-cadherin along with a conversion from an epithelial to a fibroblast-like multilayered morphology. These phenotypic changes were dependent on the activation of the Ras/MAPK pathway. However, no N-cadherin expression or downregulation of E-cadherin were detected after co-stimulation of the thyrocytes in a 3D collagen culture system even though the epithelial phenotype was lost and the cells started to invade the collagen matrix. Taken together, these results might provide important clues to the understanding of the mechanisms underlying pathological conditions such as goiter formation and thyroid cancer. Studies on the expression pattern of classical cadherins in vivo during thyroid development in mice showed that E-cadherin was expressed at high levels in thyroid cells at all developmental stages. In contrast, R-cadherin expression was induced in the embryonic thyroid coinciding with the onset of folliculogenesis, and was maintained in the adult thyroid along with E-cadherin. N-cadherin could not be detected in the thyroid primordium at any developmental stage. These findings indicate that the epithelial phenotype is maintained in thyroid progenitor cells throughout organogenesis and favor the idea that translocation of the developing thyroid might be secondary to movement of surrounding tissues.