Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases

The three iodothyronine deiodinases catalyze the metabolic pathway that removes one iodine residue from the T4 molecule, thus producing either the active T3 or the inactive metabolite rT3. Hence, deiodination is a potent mechanism by which to modulate thyroid hormone (TH) action at cellular level, thereby allowing cells to customize their own T3 availability, both spatially and temporally, irrespective of TH serum concentrations. Sonic hedgehog (Hh) regulates patterning and growth of a remarkable variety of tissues throughout embryogenesis. Its constitutive activation is associated with cancer development.

Recent evidences from two independent systems implicate the Hh signaling pathway in regulation of TH action via modulation of deiodinase expression. Interestingly, many critical developmental events, for example, amphibian metamorphosis, are tightly regulated by the TH and Hh signaling pathways. This review provides an overview of recent data referring to the intricate regulation of deiodinase activity and intracellular TH action by the Hh pathway.

This functional cross-talk provides a paradigm for interaction between two key signaling pathways critical during development and neoplastic transformation. This interaction may be relevant in other tissues and situations in which the two signaling pathways participate. Deciphering these mechanisms constitutes an exciting field for future research.