Cross-kingdom hormonal signaling: An insight from thyroid hormone functions in marine larvae

Abstract

Thyroid hormones (THs) are small, lipophilic signaling molecules built from tyrosine and iodine. TH action is well characterized in vertebrates, where these molecules play a fundamental role as regulators of development, metabolism, growth and differentiation. Increasing evidence suggests that THs also function in a variety of invertebrate species. Two alternative sources of hormone for animals are exogenous (from food items) and endogenous synthesis. We propose that exogenous THs can convey environmental information as well as regulate metabolism, revealing new communication avenues between organisms from different kingdoms. While such modes of cross-kingdom communication have been previously considered for fatty acid-based signaling and steroid hormones in plant-animal interactions, this is the first attempt to explore such a mode of action for TH signaling. We suggest that exogenous sources of TH (from food) may have been ancestral, while the ability to synthesize TH endogenously may have evolved independently in a variety of metazoans, resulting in a diversity of signaling pathways and, possibly, morphological structures involved in TH-signaling.

Full text

Many structurally similar signaling molecules are shared
between organisms from different kingdoms. For example,
oxidation products of fatty acids such as oxylipins and
eicosanoids play fundamental roles in plant and animal
metabolism, respectively (Stanley, 1999; Stoka, 1999). As
these molecules are common to both kingdoms, they can be
exploited for plant–insect recognition and manipulation
purposes (Schultz and Appel, 2004). Another group of
signaling molecules that could be involved in such a cross-
kingdom cross-talk (sensu Schultz and Appel, 2004) are
ecdysteroids. Their role in regulating insect molting and
metamorphosis is well known (Nijhout, 1994). Intriguingly the
essential precursors for ecdysteroid synthesis in insects
originate from their food, suggesting possibilities for their use
in cross-kingdom communication (for further discussion, see
Hodin, in press).
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
4355
The Journal of Experimental Biology 208, 4355-4361
Published by The Company of Biologists 2005
doi:10.1242/jeb.01877
Thyroid hormones (THs) are small, lipophilic signaling
molecules built from tyrosine and iodine. TH action is well
characterized in vertebrates, where these molecules play a
fundamental role as regulators of development,
metabolism, growth and differentiation. Increasing
evidence suggests that THs also function in a variety of
invertebrate species. Two alternative sources of hormone
for animals are exogenous (from food items) and
endogenous synthesis. We propose that exogenous THs
can convey environmental information as well as regulate
metabolism, revealing new communication avenues
between organisms from different kingdoms. While such
modes of cross-kingdom communication have been
previously considered for fatty acid-based signaling and
steroid hormones in plant–animal interactions, this is the
first attempt to explore such a mode of action for TH
signaling. We suggest that exogenous sources of TH (from
food) may have been ancestral, while the ability to
synthesize TH endogenously may have evolved
independently in a variety of metazoans, resulting in a
diversity of signaling pathways and, possibly,
morphological structures involved in TH-signaling.
Key words: thyroid hormone, mollusc, echinoderm, iodine, nuclear
hormone receptor, non-genomic action, sea urchin, Aplysia.
Summary
Review
Cross-kingdom hormonal signaling: an insight from thyroid hormone functions
in marine larvae
Andreas Heyland* and Leonid L. Moroz
The Whitney Laboratory for Marine Bioscience and Department of Neuroscience, University of Florida, FL, 32080
USA
*Author for correspondence (e-mail: aheyland@ufl.edu)
Accepted 8 September 2005
Introduction
THE JOURNAL OF EXPERIMENTAL BIOLOGY

organic iodine; and (c)the presence of receptors capable of
decoding these signals.
Below, we trace the path of organic iodine from the diet
to the targeted response. We outline the role of THs and
other organic forms of iodine within animals and plants.
Specifically, we explore the functions of TH-like molecules
as algal chemical defence and as exogenous and
endogenous signaling molecules in marine invertebrate
larvae. We hypothesize that these small, lipophilic,
vitamin-like molecules may have been exploited by a large
number of taxa as regulators of development, specifically
during metamorphosis and larval settlement (Fig.·1B).
Exogenous sources of iodine, tyrosine and thyroid
hormones for animals
Iodine distribution is highly variable among habitats
(Mairh et al., 1989). In seawater, it is part of a complex
mixture dominated by iodate and iodide at concentrations
of 40–60 parts per billion (Truesdale, 1994; Truesdale and
Upstill-Goddard, 2003). Both macro- and microalgae
accumulate significant amounts of iodine (Mairh et al.,
1989; Saenko et al., 1978; Wong et al., 2002). Some marine
algae such as kelp and microalgae contain up to 1% iodine;
the actual content can vary substantially based on the
season, water temperature and depth (Mairh et al., 1989;
Saenko et al., 1978; Wong et al., 2002). The most common
organic forms of iodine found in algae are iodomethane
(CH3I) and its derivatives, such as diiodomethane (CH2I2)
and iodobutane (C4H9I) (Collen et al., 1994). Other organic
forms of iodine, including iodotyrosines, are present in the
diatom Chaetoceras gracilis (Chino et al., 1994). Using
antibody-based detection methods, we have found that
three species of unicellular algae, Dunaliella tertiolecta,
Isochrysis aff. galbana (T-ISO) and Rhodomonas lens, also
contain thyroxine (Fig.·2). Since many marine organisms
feed on phytoplankton and algae that are rich in iodine, the
diet is a likely source of this element. It has been shown
that invertebrates and their larvae incorporate different
forms of iodine from the seawater and some have been
shown to contain various iodinated tyrosines such as T4 (L-
thyroxine), T3 (3,3⬘⬘,5-triiodo-L-thyronine), rT3 (reverse
3,3⬘⬘,5-triiodo-L-thyronine), T2 (diiodotyrosine) and T1
(monoiodotyrosine) (Eales, 1997). TH precursors and
active THs could be directly transferred from prey to
predator. Yet, the mechanisms involved in iodine uptake,
synthesis and the potential transfer of such compounds
between organisms are poorly understood.
The other critical building block of THs is tyrosine. In
animals tyrosine is synthesized from the essential dietary
amino acid phenylalanine. However, alternative routes have
been described for Cnidaria. In the sea anemone Aiptasia
pulchella (Cnidaria), tyrosine and six other amino acids
(histidine, isoleucine, leucine, lysine, phenylalanine and
valine) are transferred directly from symbiotic algae (Wang
and Douglas, 1999). Similarly, tyrosine and phenylalanine are
abundant in dissolved organic matter (DOM; Yamashita and
Tanoue, 2003). DOM includes organic compounds ranging
from macromolecules to low molecular mass compounds such
as simple organic acids and short-chain hydrocarbons, which
are dissolved in water and may be directly incorporated by
aquatic animals. Several lines of evidence suggest that DOM
may serve as a nutrient source for invertebrate larvae in marine
A. Heyland and L. L. Moroz4356
Thyroxine
Phytoplankton Zooplankton
Iodine
Organification
Ingestion
Organification
LS
EchinodermMollusc
C
B
A
I
O
O–
O
Fig.·1. (A) A hypothesis for iodine-based cross-kingdom communication
in marine ecosystems. Marine organisms incorporate iodine into an
organic matrix (organification) and synthesize thyroid hormone (TH)-
related signaling molecules, which are then shuttled through the food
chain (phytoplankton to zooplankton). This hypothesis is supported by
previously published evidence and our own new data (see Fig.·2) of TH-
like molecules being present in marine algae and various marine
invertebrates and their larval forms. (B) One functional aspect of this
cross-kingdom communication is the involvement of TH-related
compounds in development to metamorphosis of various marine
invertebrate larvae, represented schematically in B for molluscs (veliger
larvae) and echinoderms (pluteus larvae). New evidence suggests that
THs are used as developmental signals by larvae and that the primary
source may be exogenous (Chino et al., 1994; Heyland and Hodin, 2004),
although we were able to find evidence for endogenous synthesis as well
(Heyland and Hodin, 2004). The role of THs in metamorphosis per se
remains to be elucidated. The blue frame indicates larval development
(L) and the red frame metamorphic development with metamorphic
competence (C) and settlement (S). Please note that here we are using the
term THs generically for thyroid-like hormones, since the specific
chemical identification of THs in these lineages requires further
confirmation using microanalytical methods (e.g. mass spectrometry and
NMR). Images of echinoid larvae modified from Hyman (1995).
THE JOURNAL OF EXPERIMENTAL BIOLOGY

and freshwater ecosystems (Jaeckle and Manahan, 1992;
Shilling and Manahan, 1994; Thomas, 1997). In summary,
essential building blocks for TH biosynthesis are present in the
marine environment. Moreover, algae contain iodinated
tyrosines that could be transferred to marine invertebrate larvae
via the food chain. Therefore both routes of TH metabolism
outlined in Fig.·1 may occur in marine ecosystems.
Thyroid hormone metabolism and biosynthesis in
vertebrates and invertebrates
TH synthesis requires iodine to be covalently bound to
tyrosine residues. In vertebrates, ingested iodine is shuttled into
the follicle cells of the thyroid gland by the sodium iodine
symporter (NIS; Dai et al., 1996), and then into the follicular
lumen for storage and further processing. Upon recruitment,
the inorganic iodine is conjugated to thyroglobulin (TG).
Thyroid peroxidase (TPO), a large (105·kDa) heme-containing
glycoprotein, iodinates tyrosyl residues on TG (reviewed in
Nunez and Pommier, 1982). Hydrogen peroxide (H2O2) is
required for the proper transfer of iodine to the acceptor residue
via a free radical intermediate. Thyroid NADPH oxidase
appears to be the primary enzyme involved in regulated
synthesis of H2O2. Two iodinated tyrosyls are then coupled to
form THs (primarily T4). For activation of the hormone, TG
is then shuttled out of the follicular lumen into the extracellular
space on the basal side of the follicle cell via pinocytotic
vesicles. Once these vesicles reach the extracellular space,
active TH is cleaved off and released into the blood stream (for
more details on these processes see Taurog, 2000).
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 endostyle–thyroid 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
In echinoids (sea urchins and sand dollars), two forms of THs
(T4 and T3) regulate development to metamorphic competence
(Chino et al., 1994; Heyland and Hodin, 2004). Recently we
showed that thyroxine application is sufficient to change the
Cross-kingdom hormonal signaling 4357
350
250
150
50
R. lensT-I SOD. tert
[Thyroxine]
(mg dl–1 g–1 protein)
*
*
Fig.·2. Various algae species commonly used as larval nutrition in
laboratory cultures contain thyroxine. We reared replicate samples of
algae of three species [Dunaliella tertiolecta (D. tert.), Isochrysis aff.
galbana (T-ISO) and Rhodomonas lens (R. lens)] at the coastal
research center (WHOI) in Woods Hole (MA, USA) in summer 2002
in 25·l containers using protocols previously described by McEdward
and Herrera (1999), although adapted for large-scale use. Sterile
starters for all three algae species were obtained from Dr A. D.
Anderson’s laboratory (Woods Hole Oceanographic Institute, MA,
USA). After collection of replicate samples we performed
methanol:chloroform extractions and separated small molecular
species using Amicon® (Bedford, MA, USA) Ultra-15 Centrifugal
Filter Device (5·kDa) and then dried samples down in a Speed-VacTM.
We re-dissolved pellets in 50·µl 0.01·mol·l–1 NaOH and measured
thyroxine using ELISA (Total Thyroxine (Total T4) ELISA Kit Alpha
Diagnostics, San Antonio, TX, USA) following the manufacturer’s
instructions. We determined total protein content for samples using
the Micro BCATM Protein Assay Kit from Pierce (Rockford, IL,
USA). Although T-ISO has an approximately 10 times smaller cell
volume than D. tert. it contains approximately the same amount of
thyroxine [T4 standardized by protein content (mg·dl–1·g–1·protein)].
Differences in TH content of these algae may reflect differential
effects of these algae on larval development and morphogenesis.
Values are means ± 1 S.E.M.(N=3). Asterisks indicate significant
difference in hormone content between samples using Student’s t-test,
P<0.05.
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larval developmental mode of the sand dollar Leodia
sexiesperforata from an obligatory feeder to a facultative
feeder, which can complete metamorphosis and settle in the
absence of food (Heyland et al., 2004). THs not only accelerate
development in echinoids, but differentially affect larval and
juvenile morphogenesis as well. For example, while larval
development and growth are inhibited by THs, development of
juvenile structures is accelerated (Heyland and Hodin, 2004).
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
Two peroxidases, thyroid oxidase (THOX) and thyroid
peroxidase (TPO), are essential for TH synthesis in vertebrates.
THOX catalyzes the production of H2O2, which then oxidizes
the free TPO enzyme to the so called complex I. By binding
iodide, complex I is oxidized to complex II, which reacts with
tyrosyl residues of TG.
Both THOX and TPO share the primary structure of the
active site involved in heterolytic cleavage of the iron linked
O–O 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 H2O2led 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
The signaling potential of any molecule is regulated by its
synthesis and transport, and its link to a specific transduction
A. Heyland and L. L. Moroz4358
THE JOURNAL OF EXPERIMENTAL BIOLOGY

pathway. In vertebrates, TH synthesis and release are tightly
regulated via the hypothalamo–pituitary axis (HP-axis). At the
target tissue, de-iodinases can regulate the availability of T3 by
removing one iodine from T4 (Yen, 2001) One mode of signal
transduction of THs in vertebrates that is well understood is via
thyroid hormone receptors (TRs). Upon binding to its cognate
TR, T3 turns on transcription via a complex cascade of
intracellular events involving various other nuclear hormone
receptors (NRs) and co-factors (Yen, 2001). TRs have a much
higher affinity for T3 than other THs, which leads to the notion
that T3 is the active hormone and T4 is the pre-hormone.
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
THs are generally thought of as vertebrate-specific
hormones that signal via NR cascades. However, increasing
evidence suggests that TH signaling is not restricted to the
vertebrates or even chordates. TH plays a critical role in
animals that do not possess a thyroid gland or an endostyle.
Moreover, growing evidence suggests that THs generated by
food items have physiological effects on the ‘consumers’.
This may help us understand how endogenous hormone
synthesis evolved. We hypothesize that the process of TH
synthesis may have evolved through a peroxidase-dependent
defence mechanism, because these ubiquitous enzymes have
the ability to efficiently oxidize iodine. Furthermore, nuclear
hormone receptor signaling is just one of the many possible
signal transduction pathways for THs; several alternatives
may have been recruited by different metazoans. Both the
omnipresence of iodinated ligands in the marine environment
and the multitude of TH signal transduction pathways
emphasize that TH signaling has most likely evolved
independently many times among the Metazoa, and that
many more TH transduction pathways remain to be
discovered.
List of abbreviations
DOM dissolved organic matter
HP hypothalamo–pituitary
NIS sodium iodine symporter
NR nuclear receptor
rT3 reverse 3,3⬘⬘,5-triiodo-L-thyronine
T1 monoiodotyrosine
T2 diiodotyrosine
T3 3,3⬘⬘,5-triiodo-L-thyronine
T4 L-thyroxine
TG thyroglobulin
TH thyroid hormone
THOX thyroid oxidase
TPO thyroid peroxidase
TR thyroid hormone receptor
TSH thyroid stimulating hormone
We would like to thank Drs Jason Hodin, Cory Bishop and
Svetlana Maslakova as well as two anonymous reviewers,
Sami Jezzini, James Netherton III and Julian Wong, for very
helpful comments on earlier versions of the manuscript.
Cross-kingdom hormonal signaling 4359
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Furthermore we would like to thank Drs Ken Halanych, Don
Anderson and Jesus Pineda for providing research space at the
Woods Hole Oceanographic Institute. This research was
supported by NIH, NSF, Swiss National Science Foundation
Post-doctoral grant to A.H. and in part by Packard and
McKnight Foundation grants.
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