Type 3 deiodinase is critical for the maturation and function of the thyroid axis

Abstract

Developmental exposure to appropriate levels of thyroid hormones (THs) in a timely manner is critical to normal development in vertebrates. Among the factors potentially affecting perinatal exposure of tissues to THs is type 3 deiodinase (D3). This enzyme degrades THs and is highly expressed in the pregnant uterus, placenta, and fetal and neonatal tissues. To determine the physiological role of D3, we have generated a mouse D3 knockout model (D3KO) by a targeted inactivating mutation of the Dio3 gene in mouse ES cells. Early in life, D3KO mice exhibit delayed 3,5,3′-triiodothyronine (T3) clearance, a markedly elevated serum T3 level, and overexpression of T3-inducible genes in the brain. From postnatal day 15 to adulthood, D3KO mice demonstrate central hypothyroidism, with low serum levels of 3,5,3′,5′-tetraiodothyronine (T4) and T3, and modest or no increase in thyroid-stimulating hormone (TSH) concentration. Peripheral tissues are also hypothyroid. Hypothalamic T3 content is decreased while thyrotropin-releasing hormone (TRH) expression is elevated. Our results demonstrate that the lack of D3 function results in neonatal thyrotoxicosis followed later by central hypothyroidism that persists throughout life. These mice provide a new model of central hypothyroidism and reveal a critical role for D3 in the maturation and function of the thyroid axis.

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…This is also observed in animal models of transgenic Dio2 expression in the heart (273,274). In contrast, D3 inactivation results in localized increase in thyroid hormone signaling as evidenced in the D3 KO mouse (64,239,(275)(276)(277)(278)(279).…”

Thyroid hormone action during brain development: More questions than answers

“…As a consequence, thyroid hormone deficiency in the brain is not only accompanied by increased local T3 production but also by a decreased local T4 and T3 inactivation. M a n u s c r i p t 6 The significance of D3 has been highlighted by the generation of a respective knockout mouse (Hernandez et al, 2006;Hernandez et al, 2007). Among the most striking phenotypical abnormalities of these animals are a significant perinatal mortality and a strongly perturbed HPT axis that is characterized by a thyrotoxic state of the D3 knockout newborns and a central hypothyroid state of adult animals.…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…The physiological relevance of this protective mechanism is strengthened by the defective development of the D3KO mouse, which is exposed to supraphysiological amounts of thyroid hormones in utero and perinatal life, causing a significant perinatal mortality, a transient thyrotoxicosis which leads to a profound suppression of the hypothalamuspituitary-thyroid axis (102,103), similar to newborns from mothers with incomplete control of hyperthyroidism during pregnancy (104).…”