Molecular regulation of thyroid development. New mechanisms of normal and defective morphogenesis

Abstract: Congenital hypothyroidism (CH) is untreated a major cause of mental retardation. The majority of cases are due to malformations of the gland (dysgenesis). Little is known of molecular mechanisms regulating thyroid morphogenesis. Since few mutations of known thyroid transcription factors have been found among children with CH, further search for signalling pathways invloved in the pathogenesis is warranted. An overrepresentation of heart/outflow tract defects among children with thyroid dysgenesis suggests that thyroid development is mechanistically coupled to cardiovascular patterning.The aim of this thesis has been to map morphogenetic mechanisms that regulate normal thyroid development in the mouse and to identify new genes that might contribute to thyroid dysgenesis and CH. We demonstrate that the thyroid primordium maintains an epithelial differentiation throughout the translocation from the area of initial specification to its final location (Paper I). The expression pattern of classical cadherins indicates that epithelial-to-mesenchymal transition is not involved in the process. The finding of R-cadherin at late stages of development suggests a potential role in terminal histogenesis. However, we show that the thyroid develops normally both structurally and functionally in R-cadherin deficient mice (Paper II), possible due to redundancy effects of classical cadherins in the thyroid. An increased amount of adipose tissue is present in the R-cadherin knockout, suggesting that R-cadherin might influence the tissue composition of the thyroid stroma.We have further mapped the normal developmental process with particular attention to proliferative patterns and the relationship to nearby vessels (Paper IV). Thyroid shaping is closely associated with the development and maturation of the pharyngeal arch artery system and the ultimobranchial bodies. The thyroid and the ultimobranchial bodies display distinct proliferative patterns during dissociation from the endoderm and subsequent fusion. The data provide mechanistic support for the observed concurrence of thyroid dysgenesis and cardiovascular anomalies observed among children with CH.Finally, the importance of Shh and its target gene Tbx1 in thyroid development has been investigated. It is known that these genes influence patterning of the foregut (Shh) and pharyngeal apparatus (Tbx1). In Shh null embryos (Paper III) the thyroid fails to form two symmetric lobes but persist as a single body of differentiated thyroid tissue. Moreover, ectopic thyrocytes appear in the epithelium of the presumptive trachea, suggesting that Shh creates a molecular boundary for thyroid differentiation. Since Shh mRNA is not detected in the thyroid the effect on bilobation is likely non-cell-autonomous, probably related to malformations of adjacent structures such as the vascular tree. Tbx1 knockout embryos display a similar phenotype (Paper V). Only a single, severely hypoplastic thyroid lobe devoid of parafollicular C cells is present. During early development the thyroid primordium fails to establish intimate contact with the pharyngeal arch arteries, suggesting that this interaction indeed is important for the bilobation process.Taken together, the results of this thesis indicate that association between the thyroid and embryonic vessels is crucial for the normal shaping of the developing thyroid into a bilobed organ. The morphogenetic process is therefore highly dependent on the organization of adjacent structures and genes that are not expressed in the thyroid impact profoundly on its development.