MINIREVIEW Evolutionary changes to transthyretin: evolution of transthyretin biosynthesis Samantha J Richardson School of Medical Sciences, RMIT University, Bundoora, Vic., Australia Keywords amphibians; birds; brain; choroid plexus; eutherians; evolution; fish; gene regulation; liver; marsupials; monotremes; reptiles; thyroid hormones; transthyretin; vertebrates Correspondence S J Richardson, School of Medical Sciences, RMIT University, PO Box 71, Bundoora, Vic 3083, Australia Fax: +61 9925 7063 Tel: +61 9925 7897 E-mail: samantha.richardson@rmit.edu.au (Received February 2009, revised 11 June 2009, accepted 12 June 2009) Thyroid hormones are involved in growth and development, particularly of the brain Thus, it is imperative that these hormones get from their site of synthesis to their sites of action throughout the body and the brain This role is fulfilled by thyroid hormone distributor proteins Of particular interest is transthyretin, which in mammals is synthesized in the liver, choroid plexus, meninges, retinal and ciliary pigment epithelia, visceral yolk sac, placenta, pancreas and intestines, whereas the other thyroid hormone distributor proteins are synthesized only in the liver Transthyretin is synthesized by all classes of vertebrates; however, the tissue specificity of transthyretin gene expression varies widely between classes This review summarizes what is currently known about the evolution of transthyretin synthesis in vertebrates and presents hypotheses regarding tissue-specific synthesis of transthyretin in each vertebrate class doi:10.1111/j.1742-4658.2009.07244.x Introduction Thyroid hormones (THs) are essential for normal growth and development, and for regulation of the basal metabolic rate The two major thyroid hormones are 5¢,3¢,5,3-tetraiodo-[L]-thyronine (thyroxine, T4) and 3¢,5,3-triiodo-[L]-thyronine (T3) THs are synthesized by the thyroid gland and then secreted into the bloodstream (see Fig 1) In mammals, most of the TH produced by the thyroid gland is in the form of T4, which has higher affinity than T3 for the TH distributor proteins (THDPs) in the blood [1] However, T3 has higher affinity than T4 for the thyroid hormone receptors (TRs) [2] More than 99% of TH in blood is bound to THDPs, which prevent avid nonspecific partitioning of THs into membranes THs dissociate from THDPs and can enter cells via TH transporters or by passive diffusion as a result of their lipophilicity THs can be deiodinated by a family of deiodinases to either activate (T4–T3) or deactivate [T4–rT3 (reverse T3), T3–T2, etc.] THs [3] Within cells, THs bind to specific cytosolic TH-binding proteins before being translocated into the nucleus THs elicit their effects by binding to TR ⁄ RXR dimers in the nucleus, and together with co-activator or co-repressor proteins, directly modulate the expression of specific genes (see Fig 1) Many genes regulated by THs are involved in growth and development, particularly of the brain [4] Thus, normal growth and development requires tightly regulated levels of THs to reach the nucleus of cells throughout the body and brain, and a strong network of buffering and regulatory feedback systems in order Abbreviations ApoAI, apolipoprotein AI; CSF, cerebrospinal fluid; LAMP-1, lysosome-associated membrane protein; RBP, retinol-binding protein; T3, 3¢,3,5triiodo-[L]-thyronine; T4, 3¢,5¢,3,5,-tetraiodo-[L]-thyronine; TBG, thyroxine-binding globulin; TBPA, thyroxine-binding prealbumin; TH, thyroid hormone; THDP, thyroid hormone distributor protein; TLP, transthyretin-like protein; TRE, thyroid hormone response elements 5342 FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS S J Richardson Evolution of transthyretin biosynthesis Fig Five classes of TH-binding proteins The thyroid gland secreted TH (predominantly T4 in mammals) into the blood, where it binds THDPs (1) TH can dissociate from THDPs and enter cells by passive diffusion, or via TH transporter proteins (2) Within the cell, THs can be deiodinated by deiodinases (3) and bind cytosolic TH-binding proteins (4) Within the nucleus, T3 binds TH receptors (TRs) (5) NB: deiodinases D1, D2 and D3 have different locations with a cell; TRs change their conformation upon binding to DNA , albumin; , transthyretin (TTR); , TBG; , TH transporter; , deiodinase; , cytosolic TH-binding protein; , TR; , TR bound to DNA ([18] Used with permission.) to maintain euthyroid homeostasis For example, insufficient TH during gestation in humans leads to irreversible brain damage and mental retardation Many hormones affect neurogenesis in the adult brain [5] In rodents, THs are required for normal cycling of adult neural stem cells in the subventricular zone [6] A dramatic example of the effect of THs on development is the metamorphosis of tadpoles into frogs: the animal changes from an aquatic herbivore (with a long intestine) with gills and a tail, to a terrestrial carnivorous (with a short intestine) tetrapod with lungs This remarkable transition requires a finely regulated co-ordination of gene-transcription events directing apoptosis, resorption and tissue remodelling, which is driven by THs [7] This illustrates the importance of the quantitative, temporal and spatial requirements of TH distribution during development Often, the focus of TH-regulated events is on the interaction of the THs with their receptors, co-modulators and the thyroid hormone response elements (TREs) in the target genes However, this is just the final step in a long chain of events that have been quantitatively regulated at each step The movement of THs from the thyroid gland to a target cell is governed by the THDPs in the blood and cerebrospinal fluid (CSF) In humans (but not in all vertebrates or even in all mammals), the THDPs in blood are albumin, transthyretin and thyroxine-binding globulin (TBG) These three proteins are synthesized by the liver and secreted into the bloodstream Transthyretin has intermediate affinity for THs, between those for albumin (lower affinity) and TBG (higher affinity) Together, they form a buffering network system for TH distribution in the blood [8] The brain is separated from the rest of the body by a set of interfaces often referred to as ‘the blood–brain barrier’, which actually consists of four barrier interfaces [9] Only one THDP is made in the brain, namely transthyretin Transthyretin is synthesized by the epithelial cells of the choroid plexus [10], which is the blood–CSF barrier and produces most of the CSF This transthyretin is secreted exclusively into the CSF and is involved in the transport of THs from the blood into the brain and throughout the CSF [11] This review will address the evolution of transthyretin synthesis in vertebrates, specifically: the sites of transthyretin synthesis; the evolution of tissuespecific transthyretin synthesis in fish, amphibians, reptiles, birds, monotremes, marsupials and eutherians; the regulation of transthyretin gene expression; and the change of transthyretin ligand in mammals Transthyretin Transthyretin was discovered in 1942 in both human CSF [12,13] and human serum [14] It was originally named ‘prealbumin’ because it was the only plasma protein that migrated anodal to albumin during electrophoresis Transthyretin has a molecular mass of about 55 kDa and is composed of four identical subunits of about 14 kDa It was not until Ingbar used a Tris–malate buffer (rather than the then standard barbital buffer) for the electrophoretic analysis of serum that prealbumin was identified as a thyroid hormone-binding protein [15] (barbital inhibits binding of THs to transthyretin) Thus, the name was changed to ‘thyroxine-binding prealbumin’ (TBPA) A decade FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS 5343 Evolution of transthyretin biosynthesis S J Richardson later, Raz and Goodman [16] discovered that TBPA also bound retinol-binding protein (RBP) In 1981 the name was finally changed again to ‘transthyretin’, which describes its roles in the TRANSport of THYroid hormones and RETINol-binding protein [17] For details of the structure of transthyretin, see the review in this series by Dr Hennebry Transthyretin synthesis has been identified in the liver, in the choroid plexus of the brain, and in the meninges, retinal and ciliary pigment epithelia, visceral yolk sac, placenta, pancreas and intestine (see below), whereas albumin synthesis and TBG synthesis have only been identified in the liver Ligands of transthyretin To assess the selection pressures governing the regulation of tissue-specific transthyretin synthesis, the functions of transthyretin must be considered Transthyretin has multiple ligands that can be divided into two categories: ‘natural’ and ‘synthetic’ The natural ligands of transthyretin include: thyroid hormones (T3 and T4) and RBP, which itself binds retinol, metal ions, plant flavonoids, apolipoprotein AI (ApoAI) and lysosome-associated membrane protein (LAMP-1) The synthetic ligands include nonsteroidal anti-inflammatory drugs, polychlorinated biphenols, industrial pollutants and flame retardants [18] As these synthetic compounds can displace THs from transthyretin, they can act as potent endocrine disruptors Furthermore, these endocrine disruptors can be transported into the brain via binding to transthyretin synthesized by the choroid plexus and have the potential to accumulate in the brain However, as this review is focused on the evolution of transthyretin synthesis, only the natural ligands of transthyretin will be discussed For reviews on non-TH ligands of transthyretin, readers are directed to excellent reviews published previously [19–24] The function of THDPs is to ensure an even distribution of TH throughout tissues and to maintain a circulating TH pool of sufficient size in the blood and CSF [26] To determine which of the three THDPs contributes most effectively to the delivery of THs to tissues, the dissociation rates and the capillary transit times have to be considered In brief, the dissociation rates for T4 and T3 from TBG are 0.018 and 0.16 s)1, respectively; from transthyretin are 0.094 and 0.69 s)1, respectively; and from albumin are 1.3 and 2.2 s)1, respectively [27] Thus, given the capillary transit times for various tissues [28], transthyretin is responsible for much of the immediate delivery of THs to tissues [29] An analogy by Ingbar describes it quite nicely: ‘TBG is the savings account for thyroxine and TBPA is the checking account’ [30] In mammals, transthyretin, albumin and TBG have higher affinity for T4 than for T3 (see above), and, as the concentrations of both free and total T4 are higher than those of T3, T4 is often referred to as the ‘transport form’ of TH As T3 has higher affinity than T4 for the TH nuclear receptors [2], T3 is often referred to as the ‘active form’ of TH However, in birds, reptiles, amphibians and fish, transthyretin has a higher affinity for T3 than for T4 (see review in this series by Dr Prapunpoj) and these animals not have TBG in their blood Therefore, these animals could have a potentially greater ratio of T3 to T4 in their blood than mammals By contrast, in mammals, transthyretin and TBG distribute T4 (the precursor form) around the blood rather than T3 (the ‘active’ form), which binds to the nuclear receptors This allows for tissuespecific activation of T4–T3 by deiodinases, at the precise sites where T3 is required, giving a greater level of control of TH action in mammals This could be a selection pressure for the change in ligand binding of transthyretin from T3 (in fish, amphibians, reptiles and birds) to T4 (in mammals) TH In human blood, 99.97% of T4 and 99.70% of T3 is bound to the THDPs albumin, transthyretin and TBG [25] Of these, TBG has the highest affinity for T4 and T3 (1.0 · 1010 and 4.6 · 108 m)1, respectively), transthyretin has intermediate affinity (7.0 · 107 and 1.4 · 107 m)1, respectively) and albumin has the lowest affinity (7.0 · 105 and 1.0 · 105 m)1, respectively) Together, these three THDPs form a buffering network for free T4 in blood (24 pm), which could assist in protection against hypothyroidism (abnormally low levels of free TH in blood) or hyperthyroidism (abnormally high levels of free TH in blood) [8] 5344 RBP RBP was first described by Kanai et al., in 1968 [31], and was found to be bound to transthyretin in serum It was suggested that the transthyretin–RBP ⁄ retinol complex (80 kDa) or the retinol ⁄ RBP–transthyretin– RBP ⁄ retinol complex (100 kDa) prevented loss of RBP–retinol (21 kDa) via glomerular filtration in the kidneys [16] The RBP–retinol complex has higher affinity for transthyretin than apoRBP [32] The X-ray crystal structures of RBP–transthyretin complexes have demonstrated that up to two molecules of RBP can bind one tetramer of transthyretin [33] FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS S J Richardson The hypothesis that RBP binds to transthyretin to prevent loss of RBP and retinol by filtration in the kidneys may hold true for eutherians (‘placental mammals’), but it is not immediately convincing when considering other animals For example, there are two Orders of marsupials: the Diprotodonta (e.g kangaroos, koalas and wombats) and the Polyprotodonta (e.g Tasmanian devil, dunnarts and Antechinus) Adult Diprotodonta have transthyretin in their blood, whereas adult Polyprotodonta not have transthyretin in their blood [34] This raises the question as to whether there is a difference in the glomerular filtration size cut-off in diprotodont marsupials compared with that of polyprotodont marsupials Similarly, all of the species of sexually mature fish, amphibians, reptiles and monotremes studied have RBP in their blood, but not transthyretin This raises questions as to whether the glomerular filtration cut-off is significantly smaller in noneutherians, or if a plasma protein other than transthyretin fulfills the role of binding RBP to prevent its loss via the kidneys If the function of transthyretin was to prevent loss of RBP–retinol through the kidneys, one might speculate that hepatic transthyretin synthesis would have co-evolved with hepatic RBP synthesis and that genes for both transthyretin and RBP would have similar developmental and evolutionary expression patterns Evolution of transthyretin biosynthesis revealed that transthyretin is also involved in peripheral nerve regeneration [40] Choroid plexus Transthyretin is synthesized by the choroid plexus epithelial cells and secreted into the CSF [10] At least in rodents, this transthyretin is involved in the movement of T4 (but not of T3) from the blood into and within the brain, as previously reviewed [18] In addition, transthyretin synthesized by the choroid plexus and secreted into the CSF and interstitial fluid is involved in the delivery of TH to stem cells and progenitor cells within the subventricular zone of the brain [41], which requires TH for cell cycle regulation [6] The absence of transthyretin synthesized by the choroid plexus results in reduced apoptosis of progenitor cells in the subventricular zone of the adult mouse brain [41], spatial reference memory impairment [42], increased exploratory activity and reduced depressive behaviour [43], and overexpression of the neuropeptide Y phenotype [44] Reduced levels of transthyretin have been reported in the CSF of patients suffering from depression, Alzheimer’s disease and Down’s syndrome [18] In the light of reports of decreased transthyretin synthesis and secretion in the brains of ageing mammals [45], the role of transthyretin in the ageing brain requires further investigation Metal ions, plant flavonoids, ApoAI and LAMP-I The vast majority of data on transthyretin binding to metal ions [35], plant flavonoids [20], ApoAI [36] and LAMP-I [37] pertain to eutherian transthyretins Therefore, this data set is not broad enough to build hypotheses regarding selection pressures leading to the binding of these compounds by transthyretins during evolution Thus, it is not yet possible to produce a section on the influence of these ligands on the evolution of transthyretin synthesis Sites of transthyretin synthesis Visceral yolk sac Transthyretin and RBP synthesized in the visceral yolk sac of rodents has been suggested to be involved in the transport of THs and retinol from the maternal circulation to the developing fetus [46,47] Further support for this came from a previous publication [48] in which it was demonstrated that both transthyretin and RBP are secreted across the basolateral membrane towards the fetal circulation; the report also suggested that the visceral yolk sac could be the source of plasma proteins for the fetus before the fetal liver is functional Liver Placenta Transthyretin is synthesized by the liver and secreted into the blood [38], where it binds THs and RBP ⁄ retinol However, transthyretin–RBP ⁄ retinol can also be secreted from the liver as a complex [39] Thus, hepatic transthyretin is involved in the distribution of THs and retinol throughout the body via the blood The protein-bound pool of THs is believed to counteract the avid partitioning of the lipophilic THs into the lipid membranes and to maintain a circulating pool of THs in the bloodstream [26] Very recently, it has been Transthyretin synthesis by the eutherian placenta has been suggested indirectly [49] and more recently demonstrated directly [50], where it has been proposed to be involved with the transfer of THs from the mother to the fetus Retinal and ciliary pigment epithelia of the eye Transthyretin is synthesized by the retinal pigment epithelium of the eye in several eutherian species [51] FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS 5345 Evolution of transthyretin biosynthesis S J Richardson and is secreted across the apical membrane into the extracellular matrix, together with RBP that is also synthesized by the retinal pigment epithelium [52] Transthyretin and RBP synthesized by the retinal pigment epithelium have been proposed to be involved in the delivery of retinol to Muller and amacrine cells ă [52], where it is converted to retinal, which is required for photoreceptor function More recently, transthyretin synthesis by the ciliary pigment epithelium was identified, at about one-third of the levels found in the retinal pigment epithelium [53] Intestine Transthyretin synthesis has been identified in human intestines during fetal development [54], but not in the intestine of adult rats [55] A function for transthyretin synthesized by the intestine has not yet been defined However, as the intestines are extrahepatic tissue with the highest concentration of THs [56], a role for TH distribution or transport seems likely Pancreas Transthyretin synthesis in the islets of Langerhans of rat pancreas has previously been described [57] Recently, a role for transthyretin in promoting glucose-induced increases in cytoplasmic calcium ion concentration and insulin release in pancreatic beta cells has been proposed [58] A role for the transthyretin tetramer in protection against beta cell apoptosis was also proposed, having implications for type diabetes in humans Other tissues A single observation of extremely low levels of transthyretin synthesis by the meninges in rat brain has been reported [59] Transthyretin synthesis (detected by PCR) has also been identified in the skin, heart, skeletal muscle, kidney, testis, gills and pituitary in a species of adult fish (sea bream, Sparus aurata) [60] Functions for transthyretin synthesized in these tissues have not yet been identified Sites of transthyretin synthesis throughout vertebrate evolution Fish Among teleost fish, transthyretin synthesis in the whole animal has been reported during early embryogenesis in sea bream (S aurata) [60] Masu salmon (Oncorhyn5346 chus massou) synthesize transthyretin in their liver only during smoltification (a process driven by THs) [61], and subsequently Atlantic salmon (Salmo salar) and Chinook salmon (Oncorhynchus tshawytscha) were reported to undergo hepatic transthyretin synthesis only during smoltification [62] Hepatic transthyretin synthesis was also detected in 3-year-old tuna (Thunnus orientalis) [63] A comprehensive survey of tissues in adult sea bream revealed a wide distribution of transthyretin transcripts after PCR analysis (which is a more sensitive method than those used in other studies referenced) in liver, intestine, whole brain, kidney, testis, gills and pituitary However, only the signal in the liver could be confirmed by northern blotting analysis [60] Until now, there have been no published data on transthyretin synthesis by the choroid plexus of teleost fish There is an unpublished report that fish choroid plexus does not synthesize transthyretin (G Schreiber, personal communication); however, using PCR, Santos and Power [60] amplified transthyretin transcript from the whole brain of adult sea bream, which presumably contains the choroid plexus Whether this transthyretin was synthesized by the choroid plexus remains to be investigated Of the agnathan fish, two species (from two different genera) of lamprey have been studied [64] Transthyretin cDNAs were cloned and sequenced from Petromyzon marinus and Lampetra appendix These are the first transthyretin sequences from vertebrates basal to teleost fish The N-terminal regions of transthyretin subunits from both species were longer than those from other vertebrates Transthyretin was found to be synthesized in the liver of lampreys throughout their life cycles and the synthesis of transthyretin was elevated during metamorphosis In other vertebrates, a transient increase in transthyretin ⁄ THDP coincides with the increase in TH levels during development (mammals), metamorphosis (amphibians) or smoltification (fish) [62] These processes are (at least in part) driven by THs However, in these two species of lampreys, the increase in transthyretin gene expression coincides with a decrease in plasma TH levels [64] The Agnatha are at least 530 Myr old, and the function of THs in lampreys appears to be different from that in most other vertebrates, as a decrease in TH triggers metamorphosis, rather than an increase in TH concentrations [65] Accordingly, lamprey metamorphosis can also be induced by goitrogens [66] It is intriguing that in amphibians an increase in hepatic transthyretin gene expression coincides with an increase in TH concentration in the blood, which drives metamorphosis, whereas in lampreys an increase in hepatic transthyretin gene FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS S J Richardson expression is concurrent with a decrease in plasma TH concentration, which drives metamorphosis It appears that fish have a wider variety of patterns of hepatic transthyretin synthesis compared with other classes of vertebrates These patterns include: hepatic transthyretin synthesis only during times of increased TH levels in serum; hepatic transthyretin synthesis throughout the life cycle; or hepatic transthyretin synthesis throughout the life cycle but an increase during times of decreased TH levels in serum Fish comprise an extremely diverse class of vertebrates, including several highly derived lineages, which could explain the diversity of hepatic transthyretin synthesis patterns The evolutionary structural precursor to transthyretin is the transthyretin-like protein (TLP) (see the review in this series by Dr Hennebry) TLPs have been identified in all Kingdoms, but transthyretins have only been identified in the Phylum Chordata [67] The transthyretin gene probably arose as a duplication of the TLP gene around the stage of divergence of the echinoderms (see the review by Dr Hennebry) TLPs not bind THs, and at least some are involved in uric acid degradation [68] Of the vertebrate transthyretins, lamprey transthyretins are most closely related to TLPs Amphibians There are three Orders within the Class Amphibia: Anura (frogs and toads), Urodela (newts and salamanders) and Gymnophiona (caecilians) Of these, only a few species of Anura have been investigated regarding transthyretin synthesis For the amphibian species studied thus far, hepatic transthyretin synthesis occurs around the time of metamorphosis, which is driven by increased TH levels in plasma In Rana catesbieana, hepatic transthyretin synthesis was only detected just before the climax of metamorphosis [69,70], whereas in Xenopus laevis, hepatic transthyretin gene expression occurs only during metamorphosis [71] Transthyretin is not synthesized in the choroid plexus of adult or metamorphosing frogs (Limnodynastes dumerili), cane toads (Bufo marinus) [72], in X laevis tadpole brain [71], or in R catesbeiana tadpole choroid plexus [70] Reptiles There are four Orders of extant reptiles: Squamata (lizards and snakes), Chelonia (turtles and tortoises), Crocodilia (crocodiles, alligators and caimans) and Rhynchocephalia (the tuatara) Evolution of transthyretin biosynthesis Transthyretin was not detected in the blood of adult tuatara (Sphenodon punctatus), Kreft’s tortoise (Emydura kreftii), saltwater crocodile (Crocodylus porosus), stumpy-tailed lizard (Tiliqua rugosa), garden skink (Lampropholis guichenoti), or bearded dragon (Amphibolurus barbatus) [34] Transthyretin synthesis has only been detected in reptilian liver during development [62] (see the review by Dr Yamauchi in this miniseries) All four species of reptiles that were investigated – stumpy-tailed lizards (T rugosa) [73], the red-eared slider turtle (Trachemys scripta), the common snapping turtle (Chelydra serpentine) [74] and the salt-water crocodile (C porosus) [75] – were found to synthesize transthyretin in their choroid plexus Transthyretin mRNA was detected in the eyes of 1-year-old salt-water crocodiles (C porosus), but not in the liver or heart [75] Transthyretin mRNA was not detected in the liver, eye, brain (excluding choroid plexus), heart or kidney of adult stumpy-tailed lizards (T rugosa) [73] Birds Transthyretin synthesis was detected in both the choroid plexus and the liver of chickens (Gallus gallus), pigeons (Columba livia), quails (Coturnix japonica) and ducks (Anas platyrhynchos) at all ages investigated from hatching until adult [76] Transthyretin is also synthesized in the liver of adult geese (Anser anser) [34], zebra finch (Taeniopygia guttata), budgerigar (Melopsittacus undulatus), peafowl (Pavo cristatus) and penguin (Eudyptula minor novaehollandiae) (S Richardson, unpublished observations) Adult chickens (G gallus) were studied in further detail, with transthyretin mRNA detected in RNA extracts from liver, choroid plexus and eye, but not detected in lung, brain (without choroid plexus), heart, spleen, intestine, kidney or skeletal muscle [77] The group of extant birds that are believed to have branched earliest from the common lineage with reptiles are the ratites These include the emu, cassowary, ostrich and rhea Transthyretin was detected in the serum from adult emu (Dromaius novahollandiae), ostrich (Struthio camelus) [78] and rhea (Rhea americana), and also from ostrich chicks (S Richardson, unpublished observations) This suggests that as soon as the avian lineage diverged from the reptilian lineage, the transthyretin gene was expressed in the liver of adult animals Monotremes Unfortunately, there are no large breeding colonies of monotremes, which renders animals available for FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS 5347 Evolution of transthyretin biosynthesis S J Richardson investigation as scarce Hence, only adult animals have been investigated thus far Transthyretin was not detected in the serum of adult echidnas (Tachyglossus aculeatus), either during hibernation or during arousal, or from platypus (Ornithorhynchus anatinus) [34] or zaglossus (Zaglossus bruijni) (S Richardson, unpublished observation) However, transthyretin was found to be synthesized by the choroid plexus of the only monotreme investigated: the echidna [34] retin is a negative acute-phase plasma protein in marsupials (see below), and thus individuals that were not healthy or were stressed at the time of blood or liver collection could have yielded negative results because of the acute-phase response This could also explain the absence of transthyretin in D virginiana serum, investigated by David and Jurgelski For a summary of the evolutionary history and phylogenetic relationships of marsupials, see below Marsupials Eutherians Australian marsupials can be divided into two Orders: the evolutionarily older Polyprotodonta (e.g Tasmanian devil, dunnart) and the younger Diprotodonta (koala and kangaroo) Polyprotodonta are carnivores and have many teeth on their upper and lower jaws that are suitable for tearing and chewing flesh, whereas Diprotodonta are herbivores and have two large teeth on their upper and lower jaws that are suitable for grazing Concordant with their diets, Polyprotodonta have relatively short digestive tracts, whereas Diprotodonta have longer digestive tracts (These points will be referred to later in the review.) Australian polyprotodont marsupials synthesize transthyretin in their livers only during development [62] (see the review by Dr Yamauchi in this miniseries) and not as adults [34,79,80], whereas transthyretin was synthesized by the choroid plexus of all ages of marsupials investigated [34,79] By contrast, diprotodont marsupials synthesize transthyretin in their liver and choroid plexus throughout life [34,79] All American marsupials are polyprotodont and are believed to be closer to the ancestral marsupial than the Australian marsupials Synthesis of transthyretin by the choroid plexus has only been studied in one American marsupial species: the short-tailed grey opossum (Monodelphis domestica) Synthesis of transthyretin by the choroid plexus was detected during development from the day of birth [81] and in the adult [79] In 1973, Davis and Jurgelski reported that 177 Virginia opossums (Didelphis virginiana) did not have transthyretin in their serum [82] However, a more recent study has shown that M domestica, D virginiana, Caluromys lanatus (woolly opossum) and Dromiciops australis (monito del monte) have transthyretin in their blood [83] By contrast, transthyretin was not detected in serum from Marmosa sp., Metachirus sp., Chironectes sp or Philander sp However, positive controls were not available for these latter species, so these results are inconclusive as they could be false negatives [83] Similarly to the situation in eutherians, transthy- Eutherians are the group of vertebrates in which transthyretin biology has been most intensively studied, in particular rodents and humans Rats were used for the bulk of basic research carried out on transthyretin, whereas humans have been investigated in detail for normal transthyretin physiology and in particular for transthyretin-related diseases, namely the transthyretin amyloidoses Furthermore, in the past 15 years a plethora of genetically engineered mouse models for human transthyretin-related diseases have been created and investigated Perhaps some of the tissues synthesizing transthyretin in eutherians also synthesize transthyretin in other species, but this has yet to be investigated Tissues in adult eutherians known to synthesize transthyretin include: liver, choroid plexus, visceral yolk sac, placenta, retinal and ciliary pigment epithelia, pancreas and meninges Functions for transthyretin synthesized by these tissues (where known) are described above From the evolutionary perspective, a study investigating hepatic transthyretin synthesis in the eutherian Order Insectivora was carried out, as these animals are believed to be most similar to the common ancestors of eutherians and marsupials Hepatic transthyretin synthesis was detected in each species studied: shrews (Sorex ornatus californicus and Sorex araneus), hedgehogs (Erinaceus europaeus) and moles (Talpa europaea) This indicates that hepatic transthyretin gene expression in eutherians probably appeared before the diversification of eutherian lineages [84] 5348 Negative acute-phase regulation of the transthyretin gene in the liver but not in the choroid plexus Transthyretin is a typical ‘negative acute-phase plasma protein’ (i.e following trauma, surgery, inflammation or malnutrition, the transthyretin gene in the liver is down-regulated and consequently the transthyretin concentration in the blood decreases) [85] This is also the case for the albumin gene As there is only one FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS S J Richardson transthyretin gene per haploid genome in rats (and now known to be the situation for several other species), the question arose as to whether the transthyretin gene was also under negative acute-phase regulation in the choroid plexus Intriguingly, the transthyretin gene in the choroid plexus was not under negative acutephase regulation (i.e the transthyretin gene is regulated independently in the liver and in the choroid plexus) [86] As transthyretin synthesis is involved in transporting THs into the brain, as the brain is dependent on THs for normal development, as the developing and adult brain are sensitive to the effects of THs and as hepatic albumin and transthyretin are negative acutephase plasma proteins (resulting in a reduction of total circulating TH in blood during the acute phase), it was proposed that when the body is experiencing trauma or inflammation, normal rates of transthyretin gene transcription in the choroid plexus would ensure that the brain would be protected against hypothyroidism [86] As some marsupials synthesize transthyretin in their liver, an investigation into whether hepatic transthyretin gene regulation was also under negative acute-phase regulation in marsupials was carried out Following either brain surgery or injection of lipopolysaccharide, hepatic transthyretin synthesis was down-regulated in M domestica, a South American opossum [87] As the common ancestor of eutherians and marsupials is presumably more closely related to American marsupials than to Australian marsupials or to eutherians, this suggests that (at least in mammals) as soon as transthyretin is synthesized in the liver, its gene is under negative acute-phase regulation [87] A summary of the data from Costa and colleagues on the transcription factors governing tissue-specific Evolution of transthyretin biosynthesis regulation of transthyretin gene transcription in rats has been previously published [18] Transthyretin gene regulation during evolution In this section, only adult animals are considered (for regulation of the transthyretin gene during development in various classes of vertebrates, see the minireview in this series by Dr Yamauchi) The choroid plexus and liver have been investigated for transthyretin synthesis in all classes of adult vertebrates Transthyretin synthesis by other tissues has not been studied as thoroughly (usually only in eutherians or fish), hence there are insufficient data to make generalizations about the evolution of transthyretin synthesis in tissues other than the choroid plexus and the liver Liver For a comprehensive analysis, serum from adult individuals from about 150 species was analysed for the presence of THDPs All species studied were found to have albumin, and in some species (e.g fish, amphibians, reptiles and some mammals) albumin was the only THDP [34] Therefore, it was concluded that albumin is the phylogenetically oldest THDP in adult vertebrates Birds and eutherians had transthyretin in addition to albumin, and an interesting situation became apparent amongst the Australian marsupials: some had albumin as their only THDP, and others had transthyretin in addition to albumin Those that had transthyretin in serum belonged to the Order Diprotodonta, whereas those that did not have transthyretin in their serum belonged to the Order Polyprotodonta [34,80] (for an evolutionary tree based on the fossil record, see Fig 2) TBG-like proteins were detected in serum from Fig Evolutionary ⁄ developmental tree for transthyretin synthesis in the choroid plexus and liver of vertebrates Evolutionary tree showing approximate divergence times for vertebrate groups, based on the fossil record Superimposed are symbols indicating the onset of transthyretin synthesis in vertebrates ++, onset of transthyretin synthesis in the choroid plexus, in juveniles and in adults of extant species; LD, hepatic transthyretin synthesis during development only; ?LD, possible onset of hepatic transthyretin synthesis during development only; +, hepatic transthyretin synthesis during development and in adult MYA, million years ago ([62] Used with permission.) FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS 5349 Evolution of transthyretin biosynthesis S J Richardson Fig Marsupial migration in relation to the movement of tectonic plates The positions of the land masses currently known as North America (N.A.), South America (S.A.), Africa (Afr), Antarctica (Ant), India (Ind) and Australia (Aus) about 150 Ma Arrows indicate the directions of three major marsupial migrations over about 100 Myr: 1., from North America to South America; 2., from South America to North America and via Antarctica to Australia; 3., extensive radiation of marsupials within Australia (Data from [88–90] Figure from [18], used with permission.) various mammalian species, but no clear phylogeny was apparent Diprotodont marsupials have two large teeth on their upper and lower jaws and are herbivores (e.g kangaroos and wombats), whereas polyprotodont marsupials have many teeth on their upper and lower jaws and are carnivores (e.g Tasmanian devils and dunnarts) According to the fossil record, marsupials originated in the region of Laurasia, which is now North America, and were polyprotodont [88] From there, they migrated to what is now South America (for a schematic diagram of the positions of these continents about 150 Ma, see Fig 3) and those in the northern region died out From South America, some marsupials migrated back to (what is now) North America and others migrated across Gondwanaland About 45 Ma, Gondwanaland began to break up into South America, Antarctica and Australia [89] There are fossils of marsupials in Antarctica (e.g Seymour island) [90], and many marsupials were isolated on the Australian continent Shortly after the separation of Gondwanaland, there was a radiation of marsupials in Australia, which included the divergence of diprotodont marsupials from polyprotodont marsupials [88] (See Figs and 3.) It was previously suggested that in marsupials, the transthyretin gene was turned on in the liver when the ‘younger’ Diprotodonta had diverged from the ‘older’ 5350 Polyprotodonta [34,83], whereas transthyretin was synthesized in the liver as soon as the avian and eutherian lineages evolved [34,78,84] The digestive tracts of herbivorous marsupials (diprotodont) are longer than those of carnivorous marsupials (polyprotodont) [91] The intestines are the extrathyroidal tissue with the highest TH content [56], and it has been suggested that the THDPs may be responsible for the regulation of delivery of THs into the intestines [92] It was previously proposed that the increase in lipid pool (e.g length of intestine) was a selection pressure for ‘turning on’ adult hepatic transthyretin gene expression It was argued that as the transthyretin gene was already being expressed in the choroid plexus of all reptiles, birds and mammals, the onset of adult hepatic transthyretin gene expression would have simply required a change in distribution of transcription factors [8,34,93] However, more recent data on hepatic transthyretin synthesis during development [61,62,69–71], revealed that all species studied had hepatic transthyretin synthesis at some stage during development, often coinciding with an increase in serum TH concentrations In some species, hepatic transthyretin synthesis continued into adult life, whereas in other species the gene was turned off during late stages of development This led to a re-evaluation of the data and hypotheses regarding selection pressures for what was previously described as the ‘onset of adult hepatic transthyretin synthesis’, which should now be viewed as selection pressure for ‘maintaining hepatic transthyretin synthesis throughout life’ In light of this, the revised hypotheses for selection pressures for maintaining hepatic transthyretin synthesis throughout life are as follows Hypothesis Maintaining hepatic transthyretin gene expression in adulthood is related to the increase in lipid pool to body mass ratio A study by Hulbert and Else [94] compared many physiological parameters of reptiles (which not have transthyretin in their blood) and eutherians (which have transthyretin in their blood) of similar body mass Amongst other data, they showed that internal organs were larger in adult eutherians, which therefore had larger lipid pools and consequently a greater lipid volume to body mass ratio, than reptiles of a similar body weight As THs are lipophilic and preferentially partition into the lipid phase rather than the aqueous phase [95,96], the increase in the relative size of the lipid pool could have been a selection pressure for maintaining hepatic transthyretin synthesis during adult life As transthyretin has higher affinity than albumin for THs, the presence of transthyretin in the blood would contribute to ensuring a circulating pool of THs, thereby counteract- FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS S J Richardson ing the increased sink (lipid pool) for TH to potentially partition into Another example is comparison of adult Australian marsupials Diprotodont marsupials (with longer intestines) have hepatic transthyretin synthesis, whereas adult polyprotodont marsupials (with shorter intestines) not (intestines are the extrahepatic tissue with the highest concentration of TH) [56] Hypothesis Maintaining hepatic transthyretin synthesis in adulthood is related to homeothermy Transthyretin was found in serum from all studied species of birds and eutherians, which are known homeotherms (i.e they maintain their body temperature at or near 37 °C by metabolic means) However, transthyretin was not detected in serum from adult fish, amphibians, or reptiles (including members from all four extant Orders: Crocodilia, Squamata, Chelonia and Rhynchocephalia), which are ectotherms (and in whom body temperature is determined by a combination of behaviour and the environment) [8] Marsupials and monotremes are ‘poor endotherms’ (i.e their body temperatures are 25–32 °C, but when placed in cold environments, cannot maintain their body temperatures as well as ‘true endotherms’) [97] THs are intricately involved with the control of basal metabolic rate, oxygen consumption and homeothermy The basal metabolic rates for monotremes, marsupials and eutherians are approximately 140, 200 and 290 kJỈkg)0.75, respectively [97] A selection pressure for maintaining hepatic transthyretin synthesis throughout life could have been to enable the appropriate distribution of THs throughout the body to maintain homeothermy Choroid plexus Transthyretin is the major protein synthesized and secreted by the choroid plexus of reptiles, birds, monotremes, marsupials and eutherians, but is not synthesized by the choroid plexus of amphibians [8] or fish (G Schreiber, unpublished observations) [However, more recently, transthyretin mRNA has been detected in whole-brain homogenates of some fish (see above) It remains to be elucidated if this transthyretin gene expression is in the choroid plexus] It appears that the transthyretin gene in the choroid plexus was turned on once, at the stage of the stem-reptiles (the closest common ancestor to reptiles, birds and mammals), but not of amphibians and fish (see Fig 2) The early reptiles were the first to develop traces of a cerebral neocortex [98], thereby increasing their brain volume As THs are lipophilic and readily partition into cell membranes, the increase in brain size may have been the selection pressure for ‘turning on’ the transthyretin gene in the Evolution of transthyretin biosynthesis choroid plexus This resulted in transthyretin assisting movement of THs from the blood across the blood– CSF barrier into the brain, and also acting as a THDP in the CSF [8] Because hepatic transthyretin synthesis is present in all extant classes of vertebrates (including fish, amphibians and reptiles) during development, it is possible that the stem-reptiles had the transthyretin gene in their genomes, which may have been expressed in the liver during development, then a change in specificity of transcription factors could have been all that was required to activate transthyretin synthesis in the choroid plexus The major protein synthesized and secreted by the choroid plexus of juvenile and adult amphibians is the lipocalin prostaglandin D synthetase [72], also known as beta-trace [99] and Cpl1 [100] Prostaglandin D synthetase is a monomeric 20 kDa protein that belongs to the lipocalin superfamily of proteins Lipocalins have a calyx (cup) structure and are specialized in binding small molecules This raises the question of whether this lipocalin was the evolutionary functional precursor to transthyretin in the choroid plexus [This should not be confused with TLP, which is probably the evolutionary structural precursor of transthyretin (see the review in this miniseries by Dr Hennebry)] Implications of transthyretin evolving from distributing T3 to T4 It has been demonstrated that 100% of transthyretin synthesized by the choroid plexus is secreted into the CSF, and that none is secreted into the blood [11] In rats, this transthyretin was shown to transport 125I-T4 but not 125I-T3 from the blood across the blood–CSF barrier into the brain [96] However, if the transthyretin synthesized by the choroid plexus binds T3 with higher affinity than T4, as is presumably the case for birds and reptiles [78] (fish and amphibians not synthesize transthyretin in the choroid plexus), the question then arises as to whether in birds and reptiles, T3 (rather than T4) is transported across the blood–CSF barrier into the brain This also raises questions about the evolution of deiodinases in the body, and in particular in specific regions of the brain The selection pressure leading to the change from transthyretin preferentially binding T3 to T4 could be from transporting the ‘active’ form of the hormone, to transporting a ‘precursor’ form of the hormone This would allow greater flexibility and specificity at the local tissue level to either activate the T4 by deiodinating it to T3, or to inactivate the T4 by deiodinating it to rT3 This could be especially true in the brain, as in the rat FEBS Journal 276 (2009) 5342–5356 ª 2009 The Author Journal compilation ª 2009 FEBS 5351 Evolution of transthyretin biosynthesis S J Richardson brain the percentage of T3 caused by local deiodination of T4 is very specific to the region of the brain: 65% in the cortex, 51% in the cerebellum, 35% in the pons, 32% in the hypothalamus, 30% in the medulla oblongata and 22% in the spinal cord [101] It could be considered ‘safer’ to distribute a precursor form of TH around the body and into the CSF and brain, than to distribute the active form Thus, a change from binding the ‘active’ form of the hormone (T3) to the precursor form of the hormone (T4) could allow for more precise control of TH action (activation and deactivation) in specific regions of the body and brain Concluding remarks and future directions In general, transthyretin synthesis appears to be correlated to a demand for an increase in capacity for TH distribution This includes the need to counteract increasing lipid pools in both the body and the brain, and for establishment of homeothermy During development, transient transthyretin ⁄ THDP gene expression is correlated with an increase in vascular TH concentration and in TH-driven developmental events A notable exception to this is represented by the lampreys, where an increase in hepatic transthyretin synthesis is accompanied by a decrease in vascular TH concentration The change in ligand specificity of mammalian transthyretins is intriguing In this regard, mammals are the exception rather than the rule This highlights the importance of comparative biology in understanding TH metabolism As the majority of laboratory animal models are mammalian, our thinking is often skewed by the disproportionate volume of data coming from mammalian species – especially eutherian species The shift from distributing T3 to distributing T4 could have the advantage of giving a greater level of control over the regulation of TH-responsive genes, by distributing the precursor form of the hormone throughout the blood and CSF followed by local deiodination to either activate or deactivate the hormone The marsupial transthyretins represent a ‘transition’ between eutherian transthyretins and nonmammalian transthyretins in terms of ligand preference and strength of binding For this reason, it would be interesting to analyse the distribution of deiodinases in marsupials In addition, the regulation of nongenomic effects of TH in noneutherians should be considered Transthyretin synthesis in the choroid plexus is believed to have begun at the stage of the stem reptiles, about 320 Ma, which developed the first traces of a cerebral neocortex (i.e involved an increase in brain 5352 volume) It would be interesting to compare the pattern and distribution of deiodinases in the brains of adult animals not synthesizing transthyretin in choroid plexus with those that synthesize transthyretin in the choroid plexus, during development and in adulthood Similarly, comparison of patterns of deiodinases in brains of animals synthesizing transthyretin that preferentially binds T3 with those in animals where transthyretin preferentially binds T4 could give valuable insights into the evolution of cerebral TH metabolism An alternative hypothesis concerning the onset of transthyretin synthesis by the choroid plexus considers the implications of animals moving out of the water onto the land (i.e fish and amphibians not synthesize transthyretin in their choroid plexus, whereas reptiles, birds and mammals do) Iodine must be derived from the diet, and the main source of iodine is seaweed Iodine is more scarce on land than in the sea, especially in mountainous regions far from the ocean Could the onset of cerebral transthyretin synthesis be a mechanism for ensuring delivery of TH to the brain under conditions of potentially restricted iodine supply? Could the change in ligand binding from T3 to T4 be also attributed to increased storage of iodine as T4? 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T3 to T4 be also attributed to increased storage of iodine as T4? The change in temporal and spatial regulation of transthyretin gene expression throughout evolution required the evolution of. .. 2009 FEBS 5353 Evolution of transthyretin biosynthesis S J Richardson 35 Wilkinson-White LE & Easterbrook-Smith SB (2007) Characterization of the binding of Cu(II) and Zn(II) to transthyretin: