We isolated and cloned full-length cDNAs of transthyretin (TTR) from 2 genera of lamprey, Petromyzon marinus and Lampetra appendix. These sequences represent the first report of TTR sequences in vertebrates basal to teleost fishes. The deduced amino acid sequence of lamprey TTR cDNAs showed 36-47% identity with those from other vertebrates; secondary structure predictions and homology-based modeling were both consistent with TTRs from other vertebrates, and these cDNAs lacked the signatures found in TTR-like sequences of non-vertebrates. Of evolutionary interest is the observation that the N-termini of the lamprey TTR subunits are nine amino acids longer than those of eutherian TTRs and four to six amino acids longer than those from all other vertebrates. Sequencing of intron I confirmed that this longer N-terminal region is a result of the position of the intron 1/exon 2 splice site, further supporting previous studies. TTR mRNA was detected in a variety of larval lamprey tissues, with the highest levels found in the liver. TTR mRNA was also readily detected by Northern blotting, in the livers of animals at all phases of the lifecycle and was significantly elevated during metamorphosis. The upregulation of lamprey TTR gene expression during a major developmental event is consistent with observations in other vertebrates. In all other vertebrates studied to date, the transient upregulation of TTR gene expression or some other thyroid hormone distributor protein coincides with, and is thought to facilitate, the surge in serum thyroid hormone concentrations required for normal development. However, in lampreys, the upregulation of TTR gene expression occurs when serum thyroid hormone concentrations are at their lowest. (c) 2006 Elsevier Inc. All rights reserved.