Abstract
BACKGROUND: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is the most common congenital endocrine disease with a prevalence of 1:4,000 live births. We have suggested a two-hit hypothesis to explain CHTD, combining an inherited or de novo variant with a post-zygotic event. This model could explain the sporadicity of the disease (99%), its ethnic predominance and the high discordance rate between monozygotic twins. Despite years of research, more than 95% of cases of CHTD remain unexplained, especially those with thyroid ectopy. This suggests that research on genes and/or pathways not previously associated with thyroid development need to be pursued. Inactivation of the NF-κB pathway can cause deficient anterior pituitary and variable immunodeficiency, or DAVID syndrome. Whether this pathway is also involved in CHTD remains to be established. Objective: To evaluate the implication of the NF-κB pathway during thyroid migration. Methods: Knock down experiments using morpholinos in a zebrafish model were carried out to investigate the roles of certain genes related to the NF-kB pathway during thyroid development. Rescue experiment was also performed to evaluate the specificity of the morpholino. The first gene to be tested was IKBKE, a member of the inhibitor of κB kinase (IKK) family. Thyroid location was assessed by microscopy of live larvae. Results:ikbke depletion in zebrafish caused defective aortic arch artery formation and abnormal thyroid migration. The thyroid phenotype was partially rescued by injection of human IKBKE RNA in ikbke morphants. Conclusion:IKBKE seems important for normal thyroid migration suggesting that the non-canonical NF-kB pathway might be implicated. Further studies targeting other genes in this pathway are ongoing to extend these results.