The evolution of transthyretin synthesis in the choroid plexus

Choroid plexus has the highest concentration of transthyretin (TTR) mRNA in the body, 4.4 g TTR mRNA/g wet weight tissue, compared with 0.39 g in the liver. The proportion of TTR to total protein synthesis in choroid plexus is 12%. All newly synthesized TTR is secreted towards the ventricles. Net transfer of T4 occurs only towards the ventricle and depends on ongoing protein synthesis. Thyroxinebinding globulin (TBG), TTR and albumin form a buffering system for plasma [T4] because of their overlapping affinities and on/off rates for Lthyroxine (T4)binding. The individual components of this network determining T4 distribution are functionally highly redundant. Absence of TBG (humans), or TTR (mice), or albumin (humans, rats) is not associated with hypothyroidism. Natural selection is based on small, inheritable alterations improving function. The study of these alterations can identify function. TTR genes were cloned and sequenced for a large number of vertebrate species. Systematic, stepwise changes during evolution occurred only in the Nterminal region, which became shorter and more hydrophilic. Simultaneously, a change in function occurred: TTR affinities for T4 are higher in mammals than in reptiles and birds. Ltriiodothyronine (T3) affinities show the opposite trend. This favors sitespecific regulation of thyroid hormones by tissuespecific deiodinases in the brain.