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The transport of thyroxine from the bloodstream to the brain and the synthesis and secretion of transthyretin (formerly called prealbumin) were studied in rats and in sheep choroid plexus perfused in vitro. Rat choroid plexus contained 4.4 micrograms and rat liver 0.39 micrograms transthyretin mRNA per gram wet tissue. The specific radioactivity of transthyretin isolated from cerebrospinal fluid of rats 60 min after intravenous injection of [14C]leucine was greater than 50 times that of transthyretin from serum. After adding [14C]leucine to the perfusion medium of an in vitro perfused sheep choroid plexus, highly radioactive transthyretin was isolated from freshly secreted cerebrospinal fluid collected from the exposed choroid plexus surface. Secretion of newly synthesized transthyretin into the perfusion medium could not be demonstrated. After intravenous injection of [125I]-thyroxine into rats, a maximum in the curve of radioactivity in tissue plotted against time after injection was observed first for choroid plexus, thereafter for cerebrospinal fluid, and still later for cortex and striatum. Based on the obtained data, a hypothesis is derived for the mechanism of the transport of thyroid hormones from the bloodstream to the brain involving transthyretin synthesized in choroid plexus and secreted into the cerebrospinal fluid.

Transthyretin, a protein synthesized and secreted by the choroid plexus and liver, binds thyroid hormones in extracellular compartments. This binding prevents accumulation of thyroid hormones in the lipids of membranes, establishing extracellular thyroid hormone pools for the distribution of the hormones throughout the body and brain. The N-termini of the transthyretin subunits are longer and more hydrophobic in chicken than in eutherian transthyretins. Here, we show that this is a general structural feature of avian transthyretins. Systematic changes of protein structure during evolution result from selection pressure leading to changes in function. The evolution of transthyretin function, namely, the binding of thyroid hormones, was studied in nine vertebrate species. The affinity of thyroxine binding to transthyretin is lowest in avians (mean K d of about 30 nm), intermediate in metatherians (mean K d of about 17 nm) and highest in eutherians (mean K d of about 11 nm). The affinity for 3,5,3Htriiodothyronine shows an opposite trend, being four times higher for avian transthyretins than for mammalian transthyretins.

Binding of radioactive thyroxine to proteins in the plasma of vertebrates was studied by electrophoresis followed by autoradiography. Albumin was found to be a thyroxine carrier in the blood of all studied fish, amphibians, reptiles, monotremes, marsupials, eutherians (placental mammals), and birds. Thyroxine binding to transthyretin was detected in the blood of eutherians, diprotodont marsupials, and birds, but not in blood from fish, toads, reptiles, monotremes, and Australian polyprotodont marsupials. Globulins binding thyroxine were only observed in the plasma of some mammals. Apparently, albumin is the phylogenetically oldest thyroxine carrier in vertebrate blood. Transthyretin gene expression in the liver developed in parallel, and independently, in the evolutionary lineages leading to eutherians, to diprotodont marsupials, and to birds. In contrast, high transthyretin mRNA levels, strong synthesis, and secretion of transthyretin in choroid plexus from reptiles and birds indicate that transthyretin gene expression in the choroid plexus evolved much earlier than in the liver, probably at the stage of the stem reptiles. NH2-terminal sequence analysis suggests a change of transthyretin pre-mRNA splicing during evolution.

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