Studies on the potential involvement of a novel pathway in congenital hypothyroidism (CH)

An expression microarray experiment that we conducted on thyroid cells revealed that several elements of the Notch pathway are down regulated by TSH. These findings were then confirmed by RT-PCR. Immuno-histochemistry revealed the presence of Notch receptors and ligands in human and mouse thyroids. Interestingly, this pathway is involved in the regulation of cell commitment and in the development of several embryonic tissues. Genetic defects affecting the Notch signal predispose to developmental disorders, such as Alagille syndrome or congenital heart defects (CHD). Therefore, we decided to test its potential involvement in CH and in thyroid development. We obtained evidence that the Notch pathway regulates thyroid development in the zebrafish. Moreover, genetic screening revealed the presence of heterozygous missense variations affecting one of the Notch ligands in 3/13 CH patients also bearing a CHD. Finally, two different in vitro assays demonstrated that these missense variants are loss-of-function consistent with their possible involvement in the pathogenesis of these inborn errors. In conclusion, a series of experimental data obtained either in vitro and in vivo indicate for the first time that Notch pathway is involved in zebrafish thyroid morphogenesis. Moreover, genetic defects affecting this pathway may be involved in the CH pathogenesis, particularly in the cases associated with CHD.