The deiodinases and the control of intracellular thyroid hormone signaling during cellular differentiation

Abstract

Background: Thyroid hormone influences gene expression in virtually all vertebrates. Its action is initiated by the activation of T4 to T3, an outer ring deiodination reaction that is catalyzed by the type 1 or the type 2 iodothyronine selenodeiodinases (D1 or D2). Inactivation of T4 and T3 occurs via inner ring deiodination catalyzed by the type 3 iodothyronine selenodeiodinases (D3). The T4 concentration is generally quite stable in human plasma, with T3 levels also remaining constant. Deiodinase actions are tightly regulated in both pre- and post-natal life when they are required to make local adjustments of intracellular T3 concentrations in a precise spatio- and temporal manner. Although all the signals governing the dynamic expression of deiodinases in specific cell types are not known, many important regulatory factors have been deciphered.

Scope of review: This review provides striking examples from the recent literature illustrating how the expression of D2 and D3 is finely tuned during maturation of different organs, and how their action play a critical role in different settings to control intracellular T3 availability.

Major conclusions: Emerging evidence indicates that in various cell contexts, D2 and D3 are expressed in a dynamic balance, in which the expression of one enzyme is coordinately regulated with that of the other to tightly control intracellular T3 levels commensurate with cell requirements at that time.

General significance: Deiodinases control TH action in a precise spatio-temporal fashion thereby providing a novel mechanism for the local paracrine and autocrine regulation of TH action. This remarkable tissue-specific regulation of intracellular thyroid status remains hidden due to the maintenance of constant circulating TH concentrations by the hypothalamic-pituitary-thyroid axis. This article is part of a Special Issue entitled Thyroid hormone signalling.

Fig. 1

Postnatal D2 enzymatic activity in the cochlea. D2 activity is high in the early phases of postnatal cochlea maturation; it peaks at P7 and returns to basal levels by P10. Interestingly, the high D2 expression precedes the rise in cochlear T3 and T4, which indicates that local 5′ deiodination plays a critical role in the regulation of the intracellular T3 concentration.

Fig. 2

TH transporter levels in cochlea. (A) The expression of Lat1, Mct8, Mct10, and Oatp1C1 was evaluated in cochlea during embryonic development and early postnatal phases. All transporters are upregulated during postnatal growth and their expression parallels the expression of D2 mRNA (B) thereby providing the T4 substrate for D2-mediated deiodination. Oatp, organic anion-transporting polypeptide, Mct, monocarboxylate transporter, and Lat, L-type amino acid transporter.

Fig. 3

Thyroid hormone levels and myogenesis of satellite cells. In quiescence, satellite cells are a heterogeneous population of multipotent, undifferentiated cells capable of auto-renewing. The TH signal is essential for the progression into terminal differentiation, while TH downregulation is required to retain muscle progenitor cells (mpcs) in a proliferative phase. The genes identified as T3 target during myogenesis are indicated.

Fig. 4

Deiodinase expression profile during myogenesis of satellite cells. D2 and D3 show opposite expression profiles during the satellite cell differentiation program. D3 expression is sustained in the early phases of proliferation, but it declines sharply before differentiation. Conversely, D2 acts mainly in the differentiative stages, driving the TH-dependent up-regulation of several myogenic proteins.

Fig. 5

Impaired muscle regeneration in Dio2^−/−mice. (A, B) Regeneration following CTX injury is significantly delayed in Dio2^−/− mice compared with wild type animals, as shown by the high percentage of centrally located nuclei at day 15 following CTX injection. (C) D2 depletion enhances proliferation of muscle progenitor cells as demonstrated by BrdU incorporation during muscle regeneration.