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1 in Regulation of Type 1 Deiodinase Expression
Department of Human Genetics (L.L.A., A.C.-B., Z.W., D.F.)
Mount Sinai School of Medicine New York, New York 10029
Laboratory of Developmental Biology (B.V.) CMB,
Karolinska Institute Stockholm, S-17 177, Sweden
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1 and TRß, which act as
T3-dependent transcription factors, was
investigated in receptor-deficient mice. Liver and kidney D1 mRNA and
activity levels were reduced in TRß-/- but
not TR1-/- mice. Liver D1
remained weakly T3 inducible in
TRß–/– mice whereas
induction was abolished in double mutant
TR1–/–TRß–/–
mice. This indicates that TRß is primarily responsible for regulating
D1 expression whereas TR1 has only a minor role. In kidney, despite
the expression of both TR1 and TRß, regulation relied solely on
TRß, thus revealing a marked tissue restriction in TR isotype
utilization. Although TRß and TR1 mediate similar functions
in vitro, these results demonstrate differential roles in
regulating D1 expression in vivo and suggest that
tissue-specific factors and structural distinctions between TR
isotypes contribute to functional specificity. Remarkably, there was an
obligatory requirement for a TR, whether TRß or TR1, for any
detectable D1 expression in liver. This suggests a novel paradigm of
gene regulation in which the TR sets both basal expression and the
spectrum of induced states. Physiologically, these findings suggest a
critical role for TRß in regulating the thyroid hormone status
through D1-mediated metabolism. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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TRs are T3-dependent transcription factors and
belong to the family of nuclear receptors (14, 15). Distinct genes
encode the TR1 and TRß receptors, which are closely related in
their central DNA binding and C-terminal
T3-binding domains but which diverge in their N
termini. In vitro, TRs can mediate both
T3-dependent and
T3-independent transcriptional control (16, 17, 18).
TR1 and TRß can transactivate through similar
T3REs, although cotransfection assays also
suggest that they differ in their regulation of certain genes including
the TRH and pcp-2 genes (19, 20). Such distinctions may reflect TR
structural differences that confer preferences in DNA binding or
transactivation in T3RE-specific fashion (21, 22).
TR1 and TRß have both specific and common roles in
vivo, as revealed in TR-deficient mouse strains.
TR1–/– mice have a
reduced heart rate (23) whereas
TRß–/– mice exhibit deafness
and a hyperactive pituitary-thyroid axis (24).
TRß–/– mice provide a
recessive model of human resistance to thyroid hormone (RTH), which is
associated with TRß mutations (25).
TR1–/–TRß–/–
double mutant mice are runted and have an array of exacerbated
phenotypes, indicating the existence of common pathways in which TR1
and TRß cooperate with or can substitute for each other (26, 27, 28).
Here, the receptor mechanisms that regulate D1 expression in vivo were investigated using TR-deficient mice. The results show that TRß has the major role in regulating D1 expression in liver and kidney. Remarkably, the deletion of all known TRs not only abolished T3-inducibility but also abrogated basal expression of D1 in liver. Thus, the D1 gene illustrates a novel paradigm of regulation where, rather than modulating expression around a basal level determined by other factors, TRs set basal as well as T3-inducible expression. Physiologically, the findings suggest that D1 deficiency may contribute to the hormonal imbalances caused by TRß mutations in mice or in human RTH syndrome.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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30% of wild type (wt)
levels (P < 0.001), demonstrating that TRß was
required for the maintenance of basal D1 expression (Fig. 1A
). The D1 deficiency occurred despite
the approximately 3-fold elevated thyroid hormone levels (total
T4, TT4, and total
T3, TT3), reported
previously (24) (Table 1). This
emphasized the need for TRß for sustaining D1 expression as
T3 increases would normally induce D1. A similar
trend occurred in kidney, where D1 mRNA and activity levels were
reduced approximately 50% (P < 0.05) below
normal.
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1–/–
mice, liver D1 expression was not reduced but was 2-fold elevated
(P < 0.01, Fig. 1B
). In accord with the above
indicated role for TRß, this probably represents a TRß-mediated
response to the slightly elevated TT3 levels
present in TR1–/– mice
(see below) (Table 1). Kidney D1 activity was slightly (1.49-fold)
elevated in TR1–/–
mice (P < 0.01), although this was not accompanied by
corresponding increases in mRNA levels (see Fig. 3, C and D).
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1–/–TRß–/–
mice, a distinct phenotype arose that represented an extreme form of
the defect in TRß–/– mice
(Fig. 1C). Liver D1 activity fell to the detection limit and was
0.03% of normal, while mRNA levels were undetectable despite very
high TT3 levels that would normally induce D1
(Table 1) (27). The sensitivity of the Northern assay was high as
poly(A)-selected mRNA was analyzed, and prolonged exposures failed to
detect signals (see Materials and Methods), suggesting that
any putative, residual D1 mRNA expression was at very low levels. The
results indicate a requirement for either TR1 or TRß to sustain
any detectable D1 expression in liver. In contrast, kidney D1
expression was only 50–60% reduced, resembling the kidney D1
deficiency in TRß–/– mice
(see Fig. 3). Thus, unlike in liver, the additional loss of TR1 did
not significantly worsen the phenotype in
TR1–/–TRß–/–
mice, indicating a unique dependence on TRß with no detectable role
for TR1 in kidney.
D1 expression levels varied according to the genetic background of the
strains that carried the TR mutations, which differed due to the gene
targeting approaches used (see Materials and Methods). Liver
D1 activity was 3- to 4-fold greater in wild-type (wt) mice on the
129/Sv x C57BL/6J
(TRß+/+) than on the
129/OlaHsd x BALB/c
(TR1+/+) mixed
backgrounds (Fig. 1, A and B, compare left hand columns
in activity graphs). In kidney, a similar but less pronounced trend
occurred. These data are consistent with reports that D1 activity is
relatively high in the C57BL/6J strain, intermediate in a 129 substrain
(129/J), and low in the BALB/c strain (29).
Liver D1 Regulation by T3 in TR-Deficient
Mice
To investigate the TR specificity in the adaptive response of D1
expression to changes in T3 levels, TR-deficient
mice were studied under normal, hypo-, and hyperthyroid conditions.
Groups received a normal diet (ND) or were made hypothyroid using
methimazole and a low iodine diet (LID), or were made hyperthyroid with
graded doses of T3. The diet treatments produced
the expected hypo- and hyperthyroid conditions in all wt and mutant
strains (Table 1). Under ND, TT3 and
TT4 were each elevated approximately 3-fold in
TRß–/– mice and about 7- and
33-fold, respectively, in
TR1–/–TRß–/–
mice. TT4 was normal and
TT3 slightly increased in
TR1–/– mice. This
varied somewhat from free T4 and
T3 levels that were previously shown to be
marginally low and normal, respectively, in
TR1–/– mice (23),
possibly suggesting abnormalities in serum hormone binding in
TR1–/– mice.
In wt, TRß–/–, and
TR1–/– mice,
hypothyroidism suppressed liver D1 activity and mRNA levels to and
below the detection limit, respectively (Fig. 2). In
TRß+/+ mice, intermediate
hyperthyroid conditions (serum TT3 levels 10-fold
above wt normal levels) increased D1 activity 4.2-fold and mRNA
6.5-fold above normal (Fig. 2, A and B). Higher
T3 levels did not induce further increases. In
TRß–/– mice, even high
TT3 levels (84-fold above wt normal levels) only
induced D1 activity 7-fold above the very low basal levels in
TRß–/– mice
(P < 0.001). This corresponded to an absolute
activity level that was only approximately 1.5-fold above
normal levels in wt mice. Thus, liver D1 induction was severely blunted
but not abolished in TRß–/–
mice, suggesting that TRß has a major role while TR1 has a limited
role or can partially substitute for TRß.
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1–/–
mice, T3 stimulated normal increases in liver D1
expression, indicating that TR1 was nonessential for D1 induction,
in contrast to the requirement for TRß (Fig. 2, C and D). Although
the degree of increased expression was greater in
TR1+/+ than in
TRß+/+ mice, the absolute
levels attained were comparable, suggesting that the greater degree of
increase in TR1+/+ mice
was due to the lower initial D1 levels on this genetic background.
To ascertain whether the residual T3 inducibility
of D1 in TRß–/– mice was
mediated by TR1, responses to changes in T3
levels were determined in
TR1–/–TRß–/–
mice (Fig. 2, E and F). Liver D1 mRNA was undetectable and D1 activity
fell to the detection limit in
TR1–/–TRß–/–
mice under ND, a phenotype that was similar to the suppression of D1
caused by hypothyroidism in wt mice. Even high T3
doses failed to induce any detectable D1 mRNA. This indicated that
TR1 accounts for the residual basal and
T3-inducible expression of liver D1 in
TRß–/– mice.
A marginal increase in D1 activity (P < 0.05) above
the almost undetectable levels in
TR1–/–TRß–/–
mice (Fig. 4, A and B) was observed in the presence of very high
(>180-fold above normal wt levels) TT3 levels.
Although non-TR-mediated responses to T3 have
been suggested in other systems (30), this is not likely to explain the
present data given the failure of such high TT3
levels to induce a more significant D1 increase. The diminutive
increase may reflect variability in the D1 assay at the detection
limit.
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, A and B). Unlike in liver, however,
significant activity and mRNA levels were still detectable, indicating
that D1 was less sensitive to T3-dependent
regulation in kidney than in liver. In wt mice,
T3 induced dose-dependent increases in D1
expression whereas in TRß–/–
mice, no significant increase occurred, even with high
T3 doses. This total block of induction indicated
an absolute requirement for TRß for induction of kidney D1
expression. Kidney D1 expression responded normally in wt and
TR1–/– mice to changes
in T3 levels (Fig. 3, C and D). Thus, TRß but
not TR1 was essential for regulation of D1 expression in kidney.
Kidney D1 expression in
TR1–/–TRß–/–
mice under ND was reduced by approximately 50% (P <
0.001, Fig. 3, E and F), which was markedly less severe than in liver
where D1 was almost abolished (Fig. 2, E and F). Thus, in the absence
of TRs, basal expression of D1 is set at a higher level in kidney than
in liver. In wt mice under hypothyroid conditions, the suppressed D1
activity was not significantly different from the deficient values in
TR1–/–TRß–/–
mice (P > 0.78). The reduced D1 activity in
TR1–/–TRß–/–
mice did not vary significantly under any condition (P
> 0.20). In
TR1–/–TRß–/–
mice, as in TRß–/– mice,
kidney D1 expression was noninducible by T3 (Fig. 3, E and F). The absence of TR1 functions in D1 induction indicated
that TRß was solely responsible for the
T3-dependent expression of D1 in kidney.
It is noteworthy that all of the T3-dependent
regulation of D1 mRNA expression could be attributed to TRß and
TR1 in liver and to TRß in kidney. This supported the conclusion
that TRß and TR1 represent the entire complement of nuclear TRs
and argued against the existence of other hypothetical TRs in these
tissues (27, 28).
TR Gene Expression in
TR1–/– and
TRß –/– Mice
To support a direct role for TRs in D1 gene regulation, the
presence of TR1 and TRß proteins in liver and kidney was
demonstrated by electrophoretic mobility shift assay (EMSA) (27) (Fig. 4A). Using a DR4 T3RE as a probe, two
specific shifted bands were detected in wt nuclear extracts. Antibodies
against TR or retinoid X receptors (RXR) abolished or supershifted
these bands, indicating that they represented TR-RXR heterodimeric
complexes bound to the DNA. The lower TR-specific band was absent in
TR1–/– extracts, the
upper band in TRß–/–
extracts, and both bands in
TR1–/–TRß–/–
extracts, consistent with the bands representing TR1 and TRß,
respectively. Although not quantitative, the EMSA suggested that in
liver the presumptive TRß band was more abundant than that of TR1,
whereas in kidney, TR1 was somewhat more abundant.
To determine whether changes in TR1 expression in
TRß–/– mice could explain the
ability of TR1 to substitute for TRß in liver but not in kidney,
TR1 mRNA levels were investigated (Fig. 4B). Over- or
underexpression of TR1 was excluded as TR1 mRNA levels were
similar in both wt and TRß–/–
mice. T3 administration led to a slight decrease
in TR1 mRNA in liver in both wt and
TRß–/– mice, agreeing with
previous reports for rat liver (31). Conversely, TRß mRNA was not
up-regulated in the absence of TR1 (Fig. 4C), suggesting that the
normal D1 regulation in
TR1–/– mice was
achieved through normal levels of TRß. The lack of major changes in
TR1 expression in TRß–/–
mice suggested that tissue-specific differences other than changes in
TR expression levels account for the restriction of TR1 function to
liver.
Weight Changes in Hypo- and Hyperthyroidism
To rule out major differences in the general condition of
TRß–/– and
TR1–/– mice as an
influence over the D1 phenotypes, weight gain was assessed under the
hypo- and hyperthyroid treatments (Fig. 5). For wt mice, hypothyroidism produced
a decline in body weight, which was reversed with moderate
T3 doses (compare Fig. 5A to 5B and 5C). Very
high T3 doses, however, did not rescue weight
gain but typically caused further loss of weight, presumably through
hyperstimulated metabolism (Fig. 5, D, E, and F). Both
TRß–/– and
TR1–/– mouse strains
showed a similar response as wt mice, indicating that their overall
responses were not grossly impaired. The sole exception was that very
high T3 doses in
TRß–/– mice resulted in a
weight gain rather than loss (Fig. 5E). This suggested that TRß
mediated the weight loss caused by T3 excesses in
wt mice. In
TR1–/–TRß–/–
mice, neither hypo- nor hyperthyroidism produced significant changes in
weight (Fig. 5D), consistent with these mice lacking all nuclear
TRs.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1 or TRß, for any detectable D1 expression in liver.
Thus, the D1 gene in liver illustrates a novel paradigm of regulation
in which TRs set the basal expression as well as the spectrum of
T3-induced states. This contrasts with the
scenario suggested by many cotransfection and in vivo
studies in which the TR modulates expression around a basal level set
by other factors. There is less dependence on TRs in kidney where there
is substantial basal expression of D1 in the absence of TRs. Thus,
other transcription factors play a more prominent role in kidney than
in liver. This reveals differential utilization of TR signaling in the
regulation of the same gene in different tissues. On certain T3REs in vitro the TR exhibits a bimodal function, as it not only mediates T3-dependent activation but in the absence of T3, actively represses expression below basal levels (16, 17, 18). These T3-independent actions of the TR provide a possible mechanism for repression of basal transcription in hypothyroidism. For D1 expression, however, the deletion of all TRs caused an equally strong suppression as did hypothyroidism, indicating that TRs and any T3-independent function of TRs are unnecessary for suppression. Thus, models of exchange between repression and activation by the TR (32, 33) may have limited applicability in vivo and would vary depending on the target gene. Rather, the combined requirement for both the TR and T3 for any level of liver D1 expression is consistent with expression in this case being set by a continuous gradient of T3-dependent, positive activation states of the TR.
The utilization of such a positive mode of regulation, even in the
sub-basal range of expression in liver, could account for the greater
sensitivity of D1 induction in liver than in kidney (Figs. 2 and 3).
This may also confer upon the liver D1 enzyme a greater importance
in response to modest fluctuations in thyroid hormone levels. In
its highly tuned sensitivity and activation-based mode of regulation,
this role of TRs is reminiscent of that of the positively inducible
signaling pathways that activate cellular immediate early genes (34).
As these mutant mice lack TRs throughout life, it is not excluded that
uncharacterized developmental defects or other indirect changes,
involving for example, other transcription factors, contribute to the
deficiency in D1 expression.
The results demonstrate a clear TR isotype specificity in the
T3-inducible expression of D1, which is mediated
predominantly by TRß in liver and exclusively by TRß in kidney.
This cannot be explained solely by differential expression of TR
isotypes since both TRß and TR1 are expressed at levels that may
be expected to allow regulation of D1. Kidney contains relatively
abundant levels of TRß and TR1 mRNA (Fig. 4) (31, 35, 36, 37) and
T3 binding proteins, as suggested by
immunoprecipitation with antibodies against TRs (38). D1 expression is,
however, enriched in the kidney proximal tubules (39, 40). Thus,
segregation of TR isotypes in different cell types might in theory
contribute to differential regulation by TRß and TR1, although
this seems unlikely given the widespread distribution of TR1 in many
tissues. Alternatively, differences in the structure or conformation of
TR1 and TRß could result in differential recognition of the target
T3RE, exposure of activation domains, or
interaction with cofactors (33, 41). Indeed, TR1 tends to form
monomeric and TRß homodimeric DNA binding complexes (21, 22). Two
T3REs have been identified upstream of the human
D1 gene (11, 12), but these do not occur in the mouse, despite D1 being
T3 inducible in both species (42). Clarification
of the physiologically relevant T3REs may allow
investigation of the TR specificity in control of D1 expression.
The permissiveness of liver for some TR1 function occurs despite
TR1 being expressed at relatively low levels in this tissue where it
is approximately 4-fold less abundant than TRß (35, 38, 43). Several
corepressors and coactivators have been shown to modify TR activity
in vitro (32, 33, 41, 44, 45) and conceivably, tissue- or TR
isotype-specific cofactors in liver could facilitate, or in
kidney preclude, a role for TR1. A precedent may be the differential
interaction of the SMRT corepressor with retinoic acid receptors
, ß, or 
(46). Thus, intrinsic differences between TR isotypes
as well as tissue-specific factors are likely to extend the specificity
of the functions of TRß and TR1 in different physiological
situations.
Interestingly, TRß has been suggested to have the primary role in other liver functions as well as in the control of D1 expression. Thus, TRß–/– mice show defective T3-dependent regulation of cholesterol metabolism (47) and impaired T3-inducibility of malic enzyme and spot 14 mRNAs (48).
TRß is known to have a critical role in the feedback control of the
pituitary-thyroid axis and the thyroidal secretion of thyroid hormones,
as TRß–/– mice or human RTH
patients with TRß mutations have goiter and overproduce thyroid
hormones (24, 25, 49). The present study extends the functions of TRß
to regulating the thyroid hormone status at the level of the peripheral
metabolism of thyroid hormones. This raises the possibility that the
thyroid hormone excesses caused by TRß mutations are due, in part, to
D1 deficiency. RTH typically results from heterozygous TRß mutations
that generate dominant inhibitory proteins (25), and virally mediated
expression of such proteins in mice impairs the
T3-induction of liver D1 mRNA (50). Our results
predict that in RTH, any D1 deficiency would be the result of
inhibition of a TRß rather than TR1 pathway.
The consequences of D1 deficiency may be complex given that D1 has alternative activities that either convert T4 into T3 or that inactivate T3 (8). Assuming that the induction of D1 by T3 serves to protect against excesses of active hormone through the inactivating role of D1, then D1 deficiency may reduce hormone clearance rates. This could cause the accumulation of serum T4 and T3. Partial D1 deficiency, attributed to changes in the 5'-region of the D1 gene, occurs in the C3H/HeJ mouse strain (29, 51), and these mice have also been suggested to have reduced T3 clearance rates (42). It has not been ruled out that changes in D1 activity in the pituitary and thyroid glands (10, 52) or changes in type 2 or type 3 deiodinases (2, 3) also contribute to the net hormone changes in TR-deficient mice.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1 mutation was on a 129/OlaHsd x BALB/c background
(23). The strains were crossed to derive
TR1-/-TRß-/-
double mutant mice that were devoid of detectable nuclear
T3 binding capacity in brain and liver (27). wt
mice were derived with the same genetic backgrounds as each mutant
strain. Adult males, ranging in age at the start of experiments from
6–11 weeks
(TR1–/–TRß–/–)
and 6–8 weeks
(TR1–/–,
TRß–/–) were studied. Mice were
housed with 12-h light/12-h dark cycles. All animal experiments
followed approved institutional protocols.
Diet Treatments
ND-fed mice received defined pellets containing iodine at 5
mg/kg (ICN Biochemicals, Inc., Cleveland OH) and distilled
drinking water for 4 weeks. Other groups were fed the same pellets with
reduced iodine (0.05 mg/kg) and were provided with water containing
0.05% MMI and 1% potassium perchlorate (KClO4)
(LID) to induce hypothyroidism, for 4 weeks. Subgroups under LID were
made hyperthyroid by the addition of T3 at 0.5
µg/ml or 5.0 µg/ml in the drinking water containing
MMI/KClO4 (LID + T3), for
an additional 8–14 days. Given the limited numbers of
TR1–/–TRß–/–
double mutant mice available (due to fertility problems and the complex
breeding program) (27), these groups received ND, LID, or LID with only
a single T3 dose (5.0 µg/ml).
RNA Analysis
Poly (A)-selected mRNA was prepared from pooled liver or kidney
samples (TR1–/– and
TRß–/– strains, n = 5
each;
TR1–/–TRß–/–
strain, n = 3–5). Northern blots were prepared as described (36)
using as a D1 probe, a 357-bp fragment from the mouse D1 that was
cloned by RT-PCR, using primers homologous to rat D1 sequence
(5'-primer, 5'-CCGGTCGACGCTGAGATGGGGCTGCCCCAGCTATG-3'; 3'-primer,
5'-CAGCA-GGGGTCTGCTGCCTTGAATGAAATCCCAGACGTTGCA-CTT-3') (9).
Sequence analysis verified the identity of the resulting clone.
Northern lanes contained 5 µg of poly(A)-selected mRNA for all
samples except
TR1–/–TRß–/–
and their wt control samples which contained 7.5 µg. A mouse
glyceraldehyde-3-phosphodehydrogenase (G3PDH) probe was used to
ascertain integrity and quantity of RNA samples. Signals were recorded
by autoradiography (1- to 2-day exposure) and were quantified using a
Phosphorimager (Molecular Dynamics, Inc., Sunnyvale,
CA). In D1-deficient samples (from liver in
TR1–/–TRß–/–
mice and LID-treated groups) prolonged exposures (1–2 weeks) were used
but failed to detect additional signals. Moreover, spacer lanes were
used to avoid possible spillover between D1-expressing and D1-deficient
sample lanes. Spacer lanes were cut out from final figures.
D1 Enzyme Assays
Liver and kidney (n = 4–9) samples were homogenized
individually on ice in 5–6 vol of 25% (wt/vol) sucrose in 10
mM HEPES (pH 7.0) containing 10 mM
dithiothreitol (DTT) and frozen immediately. 5'-D1 activity was
determined in diluted aliquots of the homogenate by the release of
radioiodide from 10 µM
(5'-125I]rT3 (NEN Life Science Products-Dupont, Boston, MA) in the presence
of 5 mM DTT, as described previously (53). The addition of
6-n-propyl-2-thiouracil (PTU, 1 mM) inhibited activity,
thus confirming that the measured activity was that of D1 (as opposed
to PTU-resistant D2). Reactions were adjusted so that the production of
iodide was directly proportional to the incubation times (30–60 min;
prolonged times for deiodinase-deficient samples enhanced detection at
the lower limits of sensitivity). Heart, which does not normally
express D1, served as a negative control.
EMSAs
The DR4 DNA probe sequence was:
5'-GGAGCTTCAGGTCACTTCAGGTCA-AGCT-3' and the ß-fibrinogen probe was as
described (27). Nuclear protein extracts were prepared and EMSAs
performed as described previously, using the F2
T3RE (27). Supershift assays were performed with
antibodies against mouse RXR (4RX-1D12), which detect all three RXRs (a
kind gift of Dr. P. Chambon), and against full-length TRß, which
detects both TR and TRß (27).
Hormone RIAs
Blood was collected when mice were killed, and serum was
separated by centrifugation at 2000 x g and
immediately frozen. RIAs were performed for total
T3 and T4 using antibodies
(Sigma, St. Louis, MO) and
[5'-125I]-T4 and
[3'-125I]T3 (NEN Life Science Products-Dupont) tracers, as described previously
(54).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported in part by the Human Frontiers Science Program, March of Dimes Birth Defects Foundation, NIH and the Hirschl Trust (D.F.), the Swedish Cancer Foundation (B.V.), and an NIH Predoctoral Training Grant (T32-HD-07105, L.L.A.). A.C.B. received support from the Spanish Ministry of Culture and Education Grant 97 PF 00679951.
Received for publication October 6, 2000. Revision received November 20, 2000. Accepted for publication November 21, 2000.
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G. Medina-Gomez, R. M. Calvo, and M.-J. Obregon Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis Am J Physiol Endocrinol Metab, April 1, 2008; 294(4): E688 - E697. [Abstract] [Full Text] [PDF]
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J Kwakkel, W M Wiersinga, and A Boelen Interleukin-1{beta} modulates endogenous thyroid hormone receptor {alpha} gene transcription in liver cells J. Endocrinol., August 1, 2007; 194(2): 257 - 265. [Abstract] [Full Text] [PDF]
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 D C Thijssen-Timmer, M P.-T. Schiphorst, J Kwakkel, R Emter, A Kralli, W M Wiersinga, and O Bakker PGC-1{alpha} regulates the isoform mRNA ratio of the alternatively spliced thyroid hormone receptor {alpha} transcript. J. Mol. Endocrinol., October 1, 2006; 37(2): 251 - 257. [Abstract] [Full Text] [PDF]
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B. Rabier, A. J Williams, F. Mallein-Gerin, G. R Williams, and O Chassande Thyroid hormone-stimulated differentiation of primary rib chondrocytes in vitro requires thyroid hormone receptor {beta}. J. Endocrinol., October 1, 2006; 191(1): 221 - 228. [Abstract] [Full Text] [PDF]
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J Kwakkel, W M Wiersinga, and A Boelen Differential involvement of nuclear factor-{kappa}B and activator protein-1 pathways in the interleukin-1{beta}-mediated decrease of deiodinase type 1 and thyroid hormone receptor {beta}1 mRNA. J. Endocrinol., April 1, 2006; 189(1): 37 - 44. [Abstract] [Full Text] [PDF]
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 A. H. Conrad, Y. Zhang, A. R. Walker, L. A. Olberding, A. Hanzlick, A. J. Zimmer, R. Morffi, and G. W. Conrad Thyroxine Affects Expression of KSPG-Related Genes, the Carbonic Anhydrase II Gene, and KS Sulfation in the Embryonic Chicken Cornea Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 120 - 132. [Abstract] [Full Text] [PDF]
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J. Mittag, S. Friedrichsen, H. Heuer, S. Polsfuss, T. J. Visser, and K. Bauer Athyroid Pax8-/- Mice Cannot Be Rescued by the Inactivation of Thyroid Hormone Receptor {alpha}1 Endocrinology, July 1, 2005; 146(7): 3179 - 3184. [Abstract] [Full Text] [PDF]
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A. M. Zavacki, H. Ying, M. A. Christoffolete, G. Aerts, E. So, J. W. Harney, S.-y. Cheng, P. R. Larsen, and A. C. Bianco Type 1 Iodothyronine Deiodinase Is a Sensitive Marker of Peripheral Thyroid Status in the Mouse Endocrinology, March 1, 2005; 146(3): 1568 - 1575. [Abstract] [Full Text] [PDF]
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 B. J. Mengeling, F. Pan, and M. L. Privalsky Novel Mode of Deoxyribonucleic Acid Recognition by Thyroid Hormone Receptors: Thyroid Hormone Receptor {beta}-Isoforms Can Bind as Trimers to Natural Response Elements Comprised of Reiterated Half-Sites Mol. Endocrinol., January 1, 2005; 19(1): 35 - 51. [Abstract] [Full Text] [PDF]
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B Anguiano, R Rojas-Huidobro, G Delgado, and C Aceves Has the mammary gland a protective mechanism against overexposure to triiodothyronine during the peripartum period? The prolactin pulse down-regulates mammary type I deiodinase responsiveness to norepinephrine J. Endocrinol., November 1, 2004; 183(2): 267 - 277. [Abstract] [Full Text] [PDF]
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F. W. J. S. Wassen, W. Klootwijk, E. Kaptein, D. J. Duncker, T. J. Visser, and G. G. J. M. Kuiper Characteristics and Thyroid State-Dependent Regulation of Iodothyronine Deiodinases in Pigs Endocrinology, September 1, 2004; 145(9): 4251 - 4263. [Abstract] [Full Text] [PDF]
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B. Z. Doulabi, M. P.-T. Schiphorst, A. Kalsbeek, E. Fliers, O. Bakker, and W. M. Wiersinga Diurnal Variation in Rat Liver Thyroid Hormone Receptor (TR)-{alpha} Messenger Ribonucleic Acid (mRNA) Is Dependent on the Biological Clock in the Suprachiasmatic Nucleus, whereas Diurnal Variation of TR{beta}1 mRNA Is Modified by Food Intake Endocrinology, March 1, 2004; 145(3): 1284 - 1289. [Abstract] [Full Text] [PDF]
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 H. Heuer and C. A. Mason Thyroid Hormone Induces Cerebellar Purkinje Cell Dendritic Development via the Thyroid Hormone Receptor {alpha}1 J. Neurosci., November 19, 2003; 23(33): 10604 - 10612. [Abstract] [Full Text] [PDF]
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F. R. S. Freitas, A. S. Moriscot, V. Jorgetti, A. G. Soares, M. Passarelli, T. S. Scanlan, G. A. Brent, A. C. Bianco, and C. H. A. Gouveia Spared bone mass in rats treated with thyroid hormone receptor TR{beta}-selective compound GC-1 Am J Physiol Endocrinol Metab, November 1, 2003; 285(5): E1135 - E1141. [Abstract] [Full Text] [PDF]
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H. C. van Beeren, W. M. C. Jong, E. Kaptein, T. J. Visser, O. Bakker, and W. M. Wiersinga Dronerarone Acts as a Selective Inhibitor of 3,5,3'-Triiodothyronine Binding to Thyroid Hormone Receptor-{alpha}1: In Vitro and in Vivo Evidence Endocrinology, February 1, 2003; 144(2): 552 - 558. [Abstract] [Full Text] [PDF]
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P. M. Sadow, O. Chassande, K. Gauthier, J. Samarut, J. Xu, B. W. O'Malley, and R. E. Weiss Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E36 - E46. [Abstract] [Full Text] [PDF]
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 N. Vasudevan, S. Ogawa, and D. Pfaff Estrogen and Thyroid Hormone Receptor Interactions: Physiological Flexibility by Molecular Specificity Physiol Rev, October 1, 2002; 82(4): 923 - 944. [Abstract] [Full Text] [PDF]
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H. Gullberg, M. Rudling, C. Salto, D. Forrest, B. Angelin, and B. Vennstrom Requirement for Thyroid Hormone Receptor {beta} in T3 Regulation of Cholesterol Metabolism in Mice Mol. Endocrinol., August 1, 2002; 16(8): 1767 - 1777. [Abstract] [Full Text] [PDF]
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A. Flores-Morales, H. Gullberg, L. Fernandez, N. Stahlberg, N. H. Lee, B. Vennstrom, and G. Norstedt Patterns of Liver Gene Expression Governed by TR{beta} Mol. Endocrinol., June 1, 2002; 16(6): 1257 - 1268. [Abstract] [Full Text] [PDF]
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B. Zandieh Doulabi, M. Platvoet-ter Schiphorst, H. C. van Beeren, W. T. Labruyere, W. H. Lamers, E. Fliers, O. Bakker, and W. M. Wiersinga TR{beta}1 Protein Is Preferentially Expressed in the Pericentral Zone of Rat Liver and Exhibits Marked Diurnal Variation Endocrinology, March 1, 2002; 143(3): 979 - 984. [Abstract] [Full Text] [PDF]
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 A. C. Bianco, D. Salvatore, B. Gereben, M. J. Berry, and P. R. Larsen Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases Endocr. Rev., February 1, 2002; 23(1): 38 - 89. [Abstract] [Full Text] [PDF]
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F. Flamant, A.-L. Poguet, M. Plateroti, O. Chassande, K. Gauthier, N. Streichenberger, A. Mansouri, and J. Samarut Congenital Hypothyroid Pax8-/- Mutant Mice Can Be Rescued by Inactivating the TR{alpha} Gene Mol. Endocrinol., January 1, 2002; 16(1): 24 - 32. [Abstract] [Full Text] [PDF]
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A. Mansen, F. Yu, D. Forrest, L. Larsson, and B. Vennstrom TRs Have Common and Isoform-Specific Functions in Regulation of the Cardiac Myosin Heavy Chain Genes Mol. Endocrinol., December 1, 2001; 15(12): 2106 - 2114. [Abstract] [Full Text] [PDF]
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