Characterization of a major development-regulated serum thyroxine-binding globulin in the euthyroid mouse

Abstract

We confirm our finding of a major development-regulated thyroxine-binding globulin (TBG) in the serum of the euthyroid mouse and investigate a number of its binding, structural and regulatory properties. Between 16 days foetal and 60 days postnatal life, the thyroxine (T4)- and tri-iodothyronine (T3)-binding activities of the sera show a striking ontogenic pattern: the binding is 2-3 times higher in foetuses than in mothers, then further increases after birth, reaching between 3 and 5 days maximum values which are 7-8 times higher than the adult ones. This pattern is not correlated with the ontogenesis of the acknowledged specific (transthyretin, TTR) and non-specific (albumin, alpha 1-foetoprotein) thyroid-hormone carriers of the mouse sera. PAGE studies demonstrate that the protein responsible for the elevated binding of the perinatal period is an alpha 1-globulin, with a migration similar to that of human and rat TBGs. Scatchard analysis is consistent with the notions that the T4-binding sites of TBG have high association constants, about two orders of magnitude above the T4 sites of TTR (10(9) M-1 as against 10(7) M-1) and low capacities (37 and 4 nmol/g of serum proteins in pups and adults respectively). Isoelectric focusing (i.e.f.) demonstrates that mouse TBG is a microheterogeneous protein separable, as a function of the pH gradient, in up to 10-12 isoforms, Marked shifts of the relative abundance of isoforms in the course of development are evidenced. The modulation of the TBG binding activity by non-esterified fatty acids (NEFA) and the control of its synthesis by the thyroid status are also reported. Mono- and poly-unsaturated NEFAs are strong inhibitors of the TBG, although they affect TTR less readily. On the other hand, the biosynthesis and/or secretion of TBG, but not of TTR, is under thyroid-hormone control, experimental hypothyroidism inducing a marked increase of the serum TBG. The TBG of mouse behaves as a highly significant parameter of development, pointing to a likely important function of the protein in the process of maturation. Our finding of major TBGs in both euthyroid rats and mice suggests that TBG is more widely spread than was thought until now, but difficult to detect in certain species outside definite maturation stages.

Developmentally regulated thyroid hormone distributor proteins in marsupials, a reptile, and fish

“…In rats and mice, TBG is synthesised by the liver prior to the development of fur and homeothermy, and not in adulthood until senescence (36,49,50). This is a similar pattern for TBG synthesis by M.eugenii and hepatic TTR synthesis by S.crassicaudata during development.…”

Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst.

“…For example, transthyretin acts as a carrier of thyroid hormone in rodent plasma (27), and the retinol-binding protein is involved in retinol transport (28). Since vitamin A is known to be essential for normal embryonic growth as is thyroid hormone, these proteins produced by visceral endoderm may contribute to transport of maternal retinol and thyroid hormone to the developing embryo.…”

Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone.

“…T3 has a significantly shorter half-life than T4 but has more metabolic activity than thyroxin. T4 and T3 circulate bound to TTR and other plasma proteins (8,36 TTR (37). In the adult mouse, however, TTR is the major plasma carrier of T4 (8).…”

“…T4 and T3 circulate bound to TTR and other plasma proteins (8,36 TTR (37). In the adult mouse, however, TTR is the major plasma carrier of T4 (8). It was therefore of interest to measure the levels of circulating thyroid hormones in these TTR-deficient animals.…”

“…TTR is thought to have at least two functions in the adult mammal. (i) TTR possesses high-affinity binding sites for the thyroid hormones T3 and T4 (thyroxin) and is the major thyroid hormone carrier in rodent plasma (8)…”