Structure and expression of the transthyretin gene in the choroid plexus: a model for the study of the mechanism of evolution.

Thyroid hormones are key regulators of brain differentiation and function. They permeate strongly into lipid membranes. However, a substantial portion of thyroid hormone is retained in the intravascular/extracellular compartments by binding to plasma proteins. In the brain, transthyretin is the most important of these proteins. This transthyretin is synthesized in the epithelial cells of the choroid plexus and exclusively secreted towards the brain. A net movement of thyroid hormones from the blood to the brain ensues. During evolution, transthyretin synthesis in the choroid plexus and the beginnings of a neocortex first appeared at the stage of the stem reptiles. The affinity of transthyretin for thyroxine increased and that for triiodothyronine decreased during evolution. This could augment the importance of deiodination for regulation of metabolism and gene expression by thyroid hormones in the brain. Successive shifts of the splice site at the 5' end of exon 2 of transthyretin precursor mRNA in the 3' direction led to a shortening of the N-terminal sections and to an increase in hydrophilicity of the N-terminal regions of transthyretin. This shift can be explained by a sequence of single base mutations. It could be an example for a molecular mechanism of positive Darwinian evolution. The selection pressure, which led to the expression of the transthyretin gene in the choroid plexus during evolution, might have been the maintenance of thyroid hormone homeostasis in the extracellular compartment of the brain in the presence of the greatly increasing volume of the lipid phase. Copyright 2001 Wiley-Liss, Inc.