Porazzi, P., Marelli, F., Benato, F., de Filippis, T., Calebiro, D., Argenton, F., Tiso, N., and Persani, L. (2012) Disruptions of Global and Jagged1-Mediated Notch Signaling Affect Thyroid Morphogenesis in the Zebrafish. Endocrinology. 153(11):5645-5658.
The mechanisms underlying the early steps of thyroid development are largely unknown. In search for novel candidate genes
implicated in thyroid function, we performed a gene expression analysis on thyroid cells revealing that TSH regulates the
expression of several elements of the Notch pathway, including the ligand Jagged1. Because the Notch pathway is involved in
cell-fate determination of several foregut-derived endocrine tissues, we tested its contribution in thyroid development using
the zebrafish, a teleost model recapitulating the mammalian molecular events during thyroid development. Perturbing the Notch
signaling (e.g. mib mutants, γ-secretase inhibition, or Notch intracellular domain overexpression), we obtained evidence that this pathway has
a biological role during the earlier phases of thyroid primordium induction, limiting the number of cells that proceed to
a specialized fate and probably involving actions from surrounding tissues. Moreover, we were able to confirm the expression
of Jagged1 during different phases of zebrafish thyroid development, as well as in mouse and human thyroid tissues. The two
orthologues to the single jagged1 gene (JAG1) in humans, jag1a and jag1b, are expressed with different spatiotemporal patterns in the developing zebrafish thyroid. Both jag1a and jag1b morphants, as well as jag1b mutant fish line, display thyroid hypoplasia and impaired T4 production; this thyroid phenotype was rescued by coinjection of human JAG1 mRNA. In conclusion, Notch pathway is involved
in the early steps of thyroid morphogenesis, and Jagged1-Notch signal is required for zebrafish thyroid development and function.
Thus, genetic alterations affecting the Notch pathway may confer susceptibility for thyroid dysgenesis.