Cross-kingdom hormonal signaling: an insight from thyroid hormone functions in marine larvae
The Whitney Laboratory for Marine Bioscience and Department of Neuroscience, University of Florida, FL, 32080 USA
* Author for correspondence (e-mail: aheyland{at}ufl.edu)
Accepted 8 September 2005
![]() |
Summary |
---|
Key words: thyroid hormone, mollusc, echinoderm, iodine, nuclear hormone receptor, non-genomic action, sea urchin, Aplysia
![]() |
Introduction |
---|
Thyroid hormones (THs) are critical metabolic regulators in all vertebrates
(i.e. Hulbert, 2000;
Valverde-R et al., 2004
;
Yen, 2001
). Moreover THs are
well known for orchestrating amphibian and lamprey metamorphoses
(Manzon et al., 2001
;
Manzon and Youson, 1997
;
Shi et al., 1996
;
Yaoita and Brown, 1990
;
Youson, 2003
). Recent
observations suggest that THs and their metabolites are not restricted to the
vertebrates but instead are widely distributed in the animal and plant
kingdoms (Eales, 1997
;
Heyland et al., 2005
). In
fact, we have recently shown that these hormones can act via
exogenous routes as environmental messengers in echinoderm larvae
(Heyland and Hodin, 2004
), in
turn suggesting a possibility of cross-kingdom interaction.
Iodine is the essential component of THs (Fig. 1A). Two complementary routes of iodine and TH incorporation in plants and animals are illustrated in Fig. 1A. While marine invertebrate larvae may synthesize hormones endogenously from incorporated iodine (organification), it is also conceivable that their primary source of THs and their metabolites is marine phytoplankton (ingestion). These compounds, having accumulated in phytoplankton, would then be shuttled to marine invertebrate larvae that feed on algae, providing them with an enriched source of hormones and/or pre-hormones that can be more readily transformed into the active compounds. Thus, THs may be transferred through the food chain. Consequently, the utilization of iodine and its organic forms as signaling molecules would depend primarily on (a) the availability of iodine in the marine environment; (b) the recruitment of cellular machinery inside the organism capable of performing the necessary biochemical modifications of organic iodine; and (c) the presence of receptors capable of decoding these signals.
|
![]() |
Exogenous sources of iodine, tyrosine and thyroid hormones for animals |
---|
|
![]() |
Thyroid hormone metabolism and biosynthesis in vertebrates and invertebrates |
---|
Increasing evidence suggests that basal chordates (urochordates and
cephalochordates) have the ability to synthesize THs in the endostyle, a
specialized feeding organ associated with the pharynx (reviewed in
Eales, 1997). Many authors
homologize the endostyle of hemichordates, cephalochordates and urochordates
with the thyroid gland of vertebrates using developmental molecular markers
(TTF-1, TTF-2 and Pax-8, Mazet,
2002
; Ogasawara et al.,
1999b
; Ogasawara and Satou,
2003
; Ogasawara et al.,
2001
; Sasaki et al.,
2003
; Satake et al.,
2004
; Takacs et al.,
2002
; Valverde-R et al.,
2004
; Yu et al.,
2002
) and functional arguments (TPO, TG and TSH receptor,
Ogasawara, 2000
;
Ogasawara et al., 1999a
;
Shepherdley et al., 2004
;
Valverde-R et al., 2004
).
However, both the endostyle and thyroid gland are present in such basal
chordates as parasitic lampreys. The endostyle in lampreys is a larval
structure, which transforms into a thyroid gland-like organ with follicular
cells after metamorphosis (Wright and
Youson, 1976
). This suggests that the endostyles of urochordates,
cephalochordates and lampreys are homologous to each other and that the
thyroid gland evolved de novo within the vertebrate clade, therefore
at best the vertebrate thyroid or lamprey endostylethyroid complex can
only be homologized with the endostyles of urochordates and cephalochordates
at a very general level, as an organ involved in TH synthesis. Interestingly,
both the thyroid gland and endostyle are closely associated with the
pharyngeal region of the digestive tract, suggesting a link between thyroid
hormone function and food uptake.
It has been repeatedly suggested that invertebrates such as arthropods,
annelids, echinoderms and molluscs have the ability to synthesize THs and
TH-like compounds that affect the organism's physiology (reviewed in
Eales, 1997;
Heyland et al., 2005
).
However, no specific morphological structure has been associated with TH
function and synthesis in these groups and the hormone effects appear to be
extremely diverse, ranging from effects on calcium metabolism to effects on
development and reproduction (reviewed in
Eales, 1997
). Thus we propose
that THs were independently co-opted as signaling molecules in many marine
invertebrates via various structures and pathways. Initially dietary
sources of iodine and THs may have been dominant, later being replaced by
endogenous synthesis in some clades.
![]() |
Thyroid hormones as developmental signals in echinoids |
---|
These differential responses of larval and juvenile structures to TH in
echinoids are strikingly similar to the adaptive phenotypically plastic
response of these larvae to varying food concentrations
(Heyland and Hodin, 2004),
suggesting that ingested TH may be the plasticity cue in these larvae. These
findings support the hypothesis that THs from algae (i.e.
Fig. 2) provide
nutrition-related signals to echinoid larvae that alone can regulate distinct
physiological responses. While all vertebrates obtain iodine from their diet,
the direct transfer of THs (T4 and T3) across the intestinal wall has also
been observed (Wynn, 1961
).
For example, some amphibian tadpoles obtain THs from crustaceans that they
prey on. Increased TH levels in these predatory tadpoles correlate with
accelerated metamorphosis (Pfennig,
1992
). This situation could lead to a feeding preference of
tadpoles for crustaceans with high TH levels. These findings show that THs
from exogenous sources physiologically affect development an
observation in favor of the cross-kingdom (cross-phyla for the amphibian
example) communication hypothesis.
While plant-derived exogenous TH signaling may represent the ancestral mode
of thyroid metabolism in animals, evidence from echinoids suggests that some
evolved endogenous synthesis. Exposing sand dollar larvae to TH-synthesis
inhibitors delays metamorphic competence, a process that is regulated by THs.
Moreover, metamorphically inhibited larvae can be rescued with the application
of exogenous T4 (Heyland and Hodin,
2004), supporting the hypothesis of endogenous synthesis in this
group.
Endogenous TH synthesis can be advantageous because it leaves the organism independent from exogenous sources. On the other hand, it might be associated with high metabolic costs. If metabolic costs could be lowered when an existing pathway is co-opted for a novel function, it could potentially result in a wide diversity of enzymatic candidates and signaling pathways participating in TH metabolism in different organisms. In the next section we argue that candidates for endogenous TH synthesis are present in many marine invertebrate species and could have been co-opted many times independently for this function.
![]() |
The role of peroxidases in thyroid hormone biosynthesis |
---|
Both THOX and TPO share the primary structure of the active site involved
in heterolytic cleavage of the iron linked OO bond of hydrogen peroxide
(Poulos, 1988;
Poulos and Finzel, 1983
) with
other peroxidases found in protists, bacteria, plants, fungi and animals
(Taurog, 1999
). These sites
are essential to dismutate hydrogen peroxide necessary for the oxidation of
iodide (or any other halide). For example, chloroperoxidase from the mold
Caldariomyces fumago can catalyze the synthesis of significant
amounts of thyroxine from thyroglobulin and iodine
(Taurog and Howells, 1966
).
Other members of the peroxidase superfamily (sensu
Taurog, 1999
) are the
haloperoxidases found in marine algae, where they catalyze the oxidation of
halogens, a process responsible for the synthesis of small, volatile
halocarbons (Gribble,
2003
).
Animal and plant peroxidases evolved from different ancestors
(O'Brien, 2000). Their ability
to catalyze the oxidation of halogens and the synthesis of
H2O2 led to their use for various biological functions.
We hypothesize that one such function is TH synthesis in various
invertebrates. Our observations that thiourea and other TPO inhibitors block
iodine uptake (A. Heyland, unpublished) and metamorphosis
(Heyland and Hodin, 2004
) in
echinoid larvae directly support this hypothesis. However, isolation,
biochemical and pharmacological characterization of enzymes responsible for TH
synthesis in marine invertebrates will be required.
Organic forms of iodine may have been used by algae as defence against
excessive predation, or to suppress the oxidative environment inside the cell
by scavenging hydrogen peroxide and superoxide
(Collen et al., 1994;
Giese et al., 1999
). Due to
its high chemical reactivity, iodine is often rapidly neutralized to the less
reactive iodide in cells and tissues, especially in the gut
(Gosselin et al., 1984
;
Reynolds, 1989
). It is
conceivable that the aforementioned reactions involving peroxidases may have
initially served as detoxification mechanisms; the signaling role of THs may
have evolved secondarily. Under this scenario, the critical enzymes were
recruited and selected for their ability to efficiently catalyze the
subsequent reactions necessary for TH synthesis. An analogous hypothesis has
been recently suggested for the evolution of juvenile hormones as signaling
molecules in insects (Hodin, in
press
).
An ortholog of the vertebrate THOX enzyme has recently been cloned from the
sea urchin Lytechinus variegatus
(Wong et al., 2004), where its
catalytic activity induces an oxidative burst at fertilization. However,
functions in embryonic or larval development have not yet been investigated.
We are currently identifying other peroxidases in sea urchin and mollusc
larvae (A. Heyland and L. L. Moroz, unpublished data) that could be good
candidates for TH synthesis or incorporation.
![]() |
Receptors without ligands: the search for the thyroid hormone-related signal transduction pathways in marine invertebrates |
---|
To date, there is no completely characterized invertebrate TR analog.
Candidates for receptors such as CiNR1
(Carosa et al., 1998) failed to
bind DNA. Other attempts to characterize TH binding proteins in ascidians
remained ambiguous due to very low binding affinity to T3
(Fredriksson et al., 1993
).
New candidates such as putative TR from a trematode expressed sequence tags
(EST) database (CD154489) and the TR identified from the sea urchin
Strongyolentrotus purpuratus genome (GenBank, Accession number:
XM_784395) remain to be characterized molecularly and physiologically before
any statement about their identity can be made.
Structurally similar molecules can signal via radically different
pathways. Terpenoids, for example, occur as signaling molecules in plants and
animals: gibberellins (hormones regulating blooming cycle in plants) are
diterpenoids, ecdysteroids (arthropod hormones) are triterpenes and juvenile
hormones are sesquiterpenoids. Insects co-opted NRs for the signal
transduction of ecdysteroids, while plants use a variety of alternative
pathways (Thomas and Sun,
2004). The mechanistic basis for this flexibility in hormonal
signal transduction is still poorly understood. Recent efforts in
understanding how xenobiotics (environmental contaminants) can mimic hormonal
effects in animals provide evidence that low affinity binding to NRs and
receptor cross-talk between NRs is primarily involved in this physiological
interference (Mclachlan,
2001
).
It should not come as a surprise that although no NRs have been identified
in plants, fungi and bacteria (Escriva et
al., 2000), animal hormones could have relevant physiological
effects in these groups. Furthermore, we should be prepared to consider
alternative signal transduction pathways for TH action in vertebrates and
invertebrates. For example, it has become clear that THs signal via
non-genomic (also called non-nuclear or non-transcriptional) pathways in
vertebrates. This mode is characterized by relatively fast signal transduction
that does not necessarily involve protein synthesis, instead acting through a
suite of membrane-signaling pathways that may involve kinases or calmodulin
(Yen, 2001
). Two major targets
of non-genomic thyroid and steroid hormone action are the central nervous
system and the vascular system. Some recent reviews provide excellent
background information about this mode of signaling
(Simoncini and Genazzani,
2003
; Hulbert,
2000
; Davis and Davis,
1996
; Christ et al.,
1999
; Falkenstein et al.,
2000
; Schmidt et al.,
2000
).
Our knowledge about such alternative modes of signaling is still rudimentary, however, and dependent on molecular information and rigorous functional physiological manipulation of the organism, a task that is not yet easily accomplished in the majority of invertebrate species. Defining the signal transduction pathway(s) involved in TH signaling across different kingdoms may require us to broaden our view and distance ourselves from established schemes such as the signaling of THs via NR pathways.
![]() |
Conclusion and perspectives |
---|
![]() |
List of abbreviations |
---|
![]() |
Acknowledgments |
---|
![]() |
References |
---|
Carosa, E., Fanelli, A., Ulisse, S., Di Lauro, R., Rall, J. E.
and Jannini, E. A. (1998). Ciona intestinalis
nuclear receptor 1, a member of steroid/thyroid hormone receptor
family. Proc. Natl. Acad. Sci. USA
95,11152
-11157.
Chino, Y., Saito, M., Yamasu, K., Suyemitsu, T. and Ishihara, K. (1994). formation of the adult rudiment of sea-urchins is influenced by thyroid-hormones. Dev. Biol. 161, 1-11.[CrossRef][Medline]
Christ, M., Haseroth, K., Falkenstein, E. and Wehling, M. (1999). Nongenomic steroid actions: fact or fantasy? Vitam. Horm. 57,325 -373.[Medline]
Collen, J., Ekdahl, A., Abrahamsson, K. and Pedersen, M. (1994). The involvement of hydrogen-peroxide in the production of volatile halogenated compounds by Meristiella Gelidium.Phytochemistry 36,1197 -1202.[CrossRef]
Dai, G., Levy, O. and Carrasco, N. (1996). Cloning and characterization of the thyroid iodide transporter. Nature 379,458 .[CrossRef][Medline]
Davis, P. J. and Davis, F. B. (1996). Nongenomic actions of thyroid hormone. Thyroid 6, 497-504.[Medline]
Eales, J. G. (1997). Iodine metabolism and thyroid related functions in organisms lacking thyroid follicles: Are thyroid hormones also vitamins? Proc. Soc. Exp. Biol. Med. 214,302 -317.[Abstract]
Escriva, H., Delaunay, F. and Laudet, V. (2000). Ligand binding and nuclear receptor evolution. BioEssays 22,717 -727.[CrossRef][Medline]
Falkenstein, E., Tillmann, H. C., Christ, M., Feuring, M. and
Wehling, M. (2000). Multiple actions of steroid hormones
a focus on rapid, nongenomic effects. Pharmacol.
Rev. 52,513
-556.
Fredriksson, G., Lebel, J. M. and Leloup, J. (1993). Thyroid hormones and putative nuclear T3 receptors in tissues of the ascidian, Phallusia mammillata cuvier. Gen. Comp. Endocrinol. 92,379 -387.[CrossRef][Medline]
Giese, B., Laturnus, F., Adams, F. C. and Wiencke, C. (1999). Release of volatile iodinated C1-C4 hydrocarbons by marine macroalgae from various climate zones. Environ. Sci. Technol. 33,2432 -2439.[CrossRef]
Gosselin, R. E., Smith, R. P. and Hodge, H. C. (1984). Iodine: Clinical Toxicology of Commercial Products, 5th Edn. Baltimore: Williams and Wilkins.
Gribble, G. W. (2003). The diversity of naturally produced organohalogens. Chemosphere 52,289 -297.[CrossRef][Medline]
Heyland, A. and Hodin, J. (2004). Heterochronic developmental shift caused by thyroid hormone in larval sand dollars and its implications for phenotypic plasticity and the evolution of non-feeding development. Evolution 58,524 -538.[Medline]
Heyland, A., Reitzel, A. M. and Hodin, J. (2004). Thyroid hormones determine developmental mode in sand dollars (Echinodermata: Echinoidea). Evol. Dev. 6, 382-392.[CrossRef][Medline]
Heyland, A., Hodin, J. and Reitzel, A. M. (2005). Hormone signaling in evolution and development: a non-model system approach. BioEssays 27, 64-75.[CrossRef][Medline]
Hodin, J. (in press). On the origins of insect hormone signaling. In Insects and Phenotypic Plasticity, vol.II (ed. D. Whitman and T. N. Ananthakrishnan). Enfield, New Hampshire: Science Publishers, Inc.
Hulbert, A. J. (2000). Thyroid hormones and their effects: A new perspective. Biol. Rev. 75,519 -631.[CrossRef][Medline]
Hyman, L. H. (1955). The Invertebrates, vol. 4, Echinodermata. New York: McGraw Hill.
Jaeckle, W. B. and Manahan, D. T. (1992). Experimental manipulations of the organic composition of seawater implications for studies of energy budgets in marine invertebrate larvae. J. Exp. Mar. Biol. Ecol. 156,273 -284.[CrossRef]
Mairh, O. P., Ramavat, B. K., Tewari, A., Oza, R. M. and Joshi, H. V. (1989). Seasonal variation, bioaccumulation and prevention of loss of iodine in seaweeds. Phytochemistry 28,3307 -3310.[CrossRef]
Manzon, R. G. and Youson, J. H. (1997). The effects of exogenous thyroxine (T4) or triiodothyronine (T3), in the presence and absence of potassium perchlorate, on the incidence of metamorphosis and on serum T4 and T3 concentrations in larval sea lampreys (Petromyzon marinus L.). Gen. Comp. Endocrinol. 106,211 -220.[CrossRef][Medline]
Manzon, R. G., Holmes, J. A. and Youson, J. H. (2001). Variable effects of goitrogens in inducing precocious metamorphosis in sea lampreys (Petromyzon Marinus). J. Exp. Zool. 289,290 -303.[CrossRef][Medline]
Mazet, F. (2002). The fox and the thyroid: the amphioxus perspective. BioEssays 24,696 -699.[CrossRef][Medline]
Mclachlan, J. A. (2001). Environmental
signaling: What embryos and evolution teach us about endocrine disrupting
chemicals. Endocrinol. Rev.
22,319
-341.
Nijhout, H. F. (1994). Insect Hormones. New Jersey: Princeton University Press.
Nunez, J. and Pommier, J. (1982). Formation of thyroid hormones. Vitam. Horm. 39,175 -229.[Medline]
O'Brien, P. J. (2000). Peroxidases. Chem-Biol. Interact. 129,113 -139.[CrossRef][Medline]
Ogasawara, M. (2000). Overlapping expression of amphioxus homologs of the thyroid transcription factor-1 gene and thyroid peroxidase gene in the endostyle: insight into evolution of the thyroid gland. Dev. Genes Evol. 210,231 -242.[CrossRef][Medline]
Ogasawara, M. and Satou, Y. (2003). Expression of FoxE and FoxQ genes in the endostyle of Ciona intestinalis. Dev. Genes Evol. 213,416 -419.[CrossRef][Medline]
Ogasawara, M., Di Lauro, R. and Satoh, N. (1999a). Ascidian homologs of mammalian thyroid peroxidase genes are expressed in the thyroid equivalent region of the endostyle. J. Exp. Zool. 285,158 -169.[CrossRef][Medline]
Ogasawara, M., Di Lauro, R. and Satoh, N. (1999b). Ascidian homologs of mammalian thyroid transcription factor-1 gene are expressed in the endostyle. Zool. Sci. 16,559 -565.[CrossRef]
Ogasawara, M., Shigetani, Y., Suzuki, S., Kuratani, S. and Satoh, N. (2001). Expression of thyroid transcription factor-1 (TTF-1) gene in the ventral forebrain and endostyle of the agnathan vertebrate, Lampetra japonica. Genesis 30, 51-58.[CrossRef][Medline]
Pfennig, D. W. (1992). Proximate and functional causes of polyphenism in an anuran tadpole. Funct. Ecol. 6,167 -174.
Poulos, T. L. (1988). Heme enzyme crystal structures. Adv. Inorg. Biochem. 7, 1-36.
Poulos, T. L. and Finzel, B. (1983). The refined crystal structure of cytochrome C peroxidase and the 1st look at P450. Abstracts Papers Am. Chem. Soc. 185,155 -185.
Reynolds, J. E. F. (1989). Martindale, The Extra Pharmacopoeia, pp.1184 -1186. London: The Pharmaceutical Press.
Saenko, G. N., Kravtsova, Y. Y., Ivanenko, V. V. and Sheludko, S. I. (1978). Concentration of iodine and bromine by plants in seas of Japan and Okhotsk. Mar. Biol. 47,243 -250.[CrossRef]
Sasaki, A., Miyamoto, Y., Satou, Y., Satoh, N. and Ogasawara, M. (2003). Novel endostyle-specific genes in the ascidian Ciona intestinalis. Zool. Sci. 20,1025 -1030.[CrossRef][Medline]
Satake, H., Ogasawara, M., Kawada, T., Masuda, K., Aoyama,
M., Minakata, H., Chiba, T., Metoki, H., Satou, Y. and Satoh, N.
(2004). Tachykinin and tachykinin receptor of an ascidian,
Ciona intestinalis Evolutionary origin of the vertebrate
tachykinin family. J. Biol. Chem.
279,53798
-53805.
Schmidt, B. M., Gerdes, D., Feuring, M., Falkenstein, E., Christ, M. and Wehling, M. (2000). Rapid, nongenomic steroid actions: A new age? Front. Neuroendocrinol. 21, 57-94.[CrossRef][Medline]
Schultz, J. C. and Appel, H. M. (2004). Cross-kingdom cross-talk: Hormones shared by plants and their insect herbivores. Ecology 85,70 -77.
Shepherdley, C. A., Klootwijk, W., Makabe, K. W., Visser, T. J.
and Kuiper, G. (2004). An ascidian homolog of
vertebrate iodothyronine deiodinases. Endocrinology
145,1255
-1268.
Shi, Y. B., Wong, J., PuzianowskaKuznicka, M. and Stolow, M. A. (1996). Tadpole competence and tissue-specific temporal regulation of amphibian metamorphosis: Roles of thyroid hormone and its receptors. BioEssays 18,391 -399.[CrossRef][Medline]
Shilling, F. M. and Manahan, D. T. (1994).
Energy-metabolism and amino acid transport during early development of
antarctic and temperate echinoderms. Biol. Bull.
187,398
-407.
Simoncini, T. and Genazzani, A. R. (2003).
Non-genomic actions of sex steroid hormones. Eur. J.
Endocrinol. 148,281
-292.
Stanley, D. W. (1999). Eicosanoids in Invertebrate Signal Transduction Systems. Princeton: Princeton University Press.
Stoka, A. M. (1999). Phylogeny and evolution of
chemical communication: an endocrine approach. J. Mol.
Endocrinol. 22,207
-225.
Takacs, C. M., Moy, V. N. and Peterson, K. J. (2002). Testing putative hemichordate homologues of the chordate dorsal nervous system and endostyle: Expression of Nk2.1 (Ttf-1) in the acorn worm Ptychodera Flava (Hemichordata, Ptychoderidae). Evol. Dev. 4,405 -417.[CrossRef][Medline]
Taurog, A. (1999). Molecular evolution of thyroid peroxidase. Biochimie 81,557 -562.[CrossRef][Medline]
Taurog, A. (2000). Hormone synthesis: thyroid iodine metabolism. In The Thyroid (ed. L. E. Braverman and R. D. Utiger), pp. 61-85. Philadelphia: Lippincott Williams & Wilkins.
Taurog, A. and Howells, E. M. (1966). Enzymatic
iodination of tyrosine and thyroglobulin with chloroperoxidase. J.
Biol. Chem. 241,1329
-1335.
Thomas, J. D. (1997). The role of dissolved organic matter, particularly free amino acids and humic substances, in freshwater ecosystems. Freshw. Biol. 38, 1-36.[CrossRef]
Thomas, S. G. and Sun, T. P. (2004). Update on
gibberellin signaling. A tale of the tall and the short. Plant
Physiol. 135,668
-676.
Truesdale, V. W. (1994). Distribution of dissolved iodine in the Irish sea, a temperate shelf sea. Estuar. Coast. Shelf Sci. 38,435 -446.[CrossRef]
Truesdale, V. W. and Upstill-Goddard, R. (2003). Dissolved iodate and total iodine along the British east coast. Estuar. Coast. Shelf Sci. 56,261 -270.[CrossRef]
Valverde-R, C., Orozco, A., Becerra, A., Jeziorski, M. C., Villalobos, P. and Solis-S, J. C. (2004). Halometabolites and cellular dehalogenase systems: An evolutionary perspective. Int. Rev. Cytol. 234,143 -199.[Medline]
Wang, J. T. and Douglas, A. E. (1999). Essential amino acid synthesis and nitrogen recycling in an alga-invertebrate symbiosis. Mar. Biol. 135,219 -222.[CrossRef]
Wong, G. T. F., Piumsomboon, A. U. and Dunstan, W. M. (2002). The transformation of iodate to iodide in marine phytoplankton cultures. Mar. Ecol. Prog. Ser. 237, 27-39.
Wong, J. L., Creton, R. and Wessel, G. M. (2004). The oxidative burst at fertilization is dependent upon activation of the dual oxidase Udx1. Dev. Cell 7, 801-814.[CrossRef][Medline]
Wright, G. M. and Youson, J. H. (1976). Transformation of endostyle of anadromous sea lamprey, Petromyzon marinus L., during metamorphosis light-microscopy and autoradiography with I125. Gen. Comp. Endocrinol. 30,243 -257.[CrossRef][Medline]
Wynn, J. O. (1961). Components of the serum protein-bound iodine following administration of I-131-labeled hog thyroglobulin. J. Clin. Endocrinol. Metab. 21,1572 -1578.[Medline]
Yamashita, Y. and Tanoue, E. (2003). Distribution and alteration of amino acids in bulk DOM along a transect from bay to oceanic waters. Mar. Chem. 82,145 -160.[CrossRef]
Yaoita, Y. and Brown, D. D. (1990). A correlation of thyroid hormone receptor gene expression with amphibian metamorphosis. Genes Dev. 4,1917 -1924.[Abstract]
Yen, P. M. (2001). Physiological and molecular
basis of thyroid hormone action. Physiol. Rev.
81,1097
-1142.
Youson, J. H. (2003). The impact of environmental and hormonal cues on the evolution of fish metamorphosis. In Environment, Development, and Evolution: Toward a Synthesis (ed. B. K. Hall, R. D. Pearson and G. B. Müller), pp. 239-277. Cambridge, London: MIT Press.
Yu, J. K., Holland, N. D. and Holland, L. Z. (2002). An amphioxus winged Helix/Forkhead gene, Amphifoxd: Insights into vertebrate neural crest evolution. Dev. Dyn. 225,289 -297.[CrossRef][Medline]