Deiodinases: How Nonmammalian Research Helped Shape Our Present View

Abstract

Iodothyronine deiodinases are enzymes capable of activating and inactivating thyroid hormones (THs) and have an important role in regulating TH action in tissues throughout the body. Three types of deiodinases (D1, D2, and D3) were originally defined based on their biochemical characteristics. Cloning of the first complementary DNAs in the 1990s (Dio1 in rat and dio2 and dio3 in frog) allowed to confirm the existence of 3 distinct enzymes. Over the years, increasing genomic information revealed that deiodinases are present in all chordates, vertebrates, and nonvertebrates and that they can even be found in some mollusks and annelids, pointing to an ancient origin. Research in nonmammalian models has substantially broadened our understanding of deiodinases. In relation to their structure, we discovered for instance that biochemical properties such as inhibition by 6-propyl-2-thiouracil, stimulation by dithiothreitol, and temperature optimum are subject to variation. Data from fish, amphibians, and birds were key in shifting our view on the relative importance of activating and inactivating deiodination pathways and in showing the impact of D2 and D3 not only in local but also whole body T3 availability. They also led to the discovery of new local functions such as the acute reciprocal changes in D2 and D3 in hypothalamic tanycytes upon photostimulation, involved in seasonal rhythmicity. With the present possibilities for rapid and precise gene silencing in any species of interest, comparative research will certainly further contribute to a better understanding of the importance of deiodinases for adequate TH action, also in humans.

Keywords: deiodinase; development; evolution; function; vertebrates.

Figure 1.

Phylogenetic tree showing the evolutionary relationship between the different groups of chordates mentioned in the text.

Figure 2.

Changes in plasma T₄ and T₃ and in vitro hepatic D1 and D3 activity during the last week of chicken embryonic development. Graphs show average values of data taken from 2 studies (41, 43). Abbreviations: C1, 1-day-old chick; E14-E19, embryos of 14-19 days old; H, day of hatching.

Figure 3.

Expression of deiodinases at the brain barriers in 8-day-old chicken embryos. In situ hybridization shows DIO2 expression in the developing capillaries of the blood-brain barrier while DIO3 is highly expressed in the developing choroid plexus at the blood-cerebrospinal fluid barrier. Scale bar 100 µm for both pictures.

Figure 4.

Knockdown of the TH activating (D1+D2) or the inactivating (D3) pathway in developing zebrafish by antisense morpholino (MO). Both knockdown conditions disturb normal development, but the impact of blocking D3 activity is more severe. (A) Larvae at 4 days postfertilization. Arrows point to impact on eye, ear and swim bladder development. (B) Free swimming behavior and reaction to a light pulse at 3 days postfertilization. Abbreviations: D1D2MO: combined injection of dio1- and dio2-blocking MOs, D3MO: injection of dio3b-blocking MO; SCMO: injection of standard control MO.