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Thyroid Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (H.M.T., T.B., D.S., P.R.L.), Boston, Massachusetts 02115; Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine (G.L., R.M.L.), and Department of Neuroscience, Tufts University School of Medicine (R.M.L.), Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: P. Reed Larsen, M.D., Thyroid Division, Harvard Institute of Medicine, #560, 77 Louis Pasteur Avenue, Boston, Massachusetts 02115.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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D3 is a selenoenzyme initially identified as a complementary DNA (cDNA) with significant nucleotide similarity to D1, which was enriched in a subtraction library prepared from T3-treated Xenopus laevis tadpoles (8). Other strategies have resulted in the cloning of D3 cDNAs from Rana catesbeiana, rat, human, and chicken (2, 9, 10, 11). In their original studies, Kaplan and Yaskowski showed that D3 activity in the central nervous system was positively correlated with thyroid status, in contrast to that of type 2 deiodinase (D2) which changes in the opposite direction (12, 13, 14). This led to the concept that T3 homeostasis in the central nervous system is a function of reciprocal compensatory changes in D3 and D2 activities. In the cortex and cerebellum from hypothyroid rats, compensatory decreases in D3 activity appear to be quantitatively as important as the increases in D2 activity in maintaining T3 concentrations constant in these tissues (15, 16). In the rat, D3 is expressed primarily in astroglial cells, and its activity in culture systems increases in response to thyroid hormone, retinoids, cAMP, phorbol esters, and fibroblast growth factor (8, 17, 18, 19).
Despite the critical role played by D3 in T3 homeostasis in the central nervous system, it is not known where in this tissue the enzyme is expressed, nor is it clear whether the response of D3 to T3 in the central nervous system is local or general. Recent studies have shown, for example, that the expression of D2 is highly localized to the tanycytes lining the lower portions of the third ventricle (20, 21). The present studies were initiated to evaluate the localization of D3 messenger RNA (mRNA) expression in the rat central nervous system using in situ hybridization techniques and to determine the qualitative and quantitative aspects of the response of D3 mRNA in this tissue to alterations in thyroid status using Northern analysis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For Northern analysis with polyadenylated [poly(A)+] RNA, male Harlan Sprague-Dawley, Inc. rats (Harlan Sprague-Dawley, Inc., Indianapolis, IN), weighing 125–200 g, were used. Animals were maintained at the Center for Animal Resources and Comparative Medicine at Harvard Medical School and were untreated (euthyroid) or T3 treated (hyperthyroid) as described. Animals were killed by pentobarbital or CO2 anesthesia, and various brain regions were removed quickly and frozen in liquid nitrogen. At the time of death, animals weighed 160–250 g (euthyroid) or 193–226 g (T3 treated).
In situ hybridization histochemistry
For in situ hybridization histochemistry, four
animals in each of the three groups were weighed, overdosed with
pentobarbital, and perfused through the ascending aorta with 0.01
M PBS, pH 7.2, containing 15,000 U/liter heparin sulfate
for 30–60 sec, followed by 4% paraformaldehyde in PBS for 15 min.
Venous blood was collected from the inferior vena cava for measurement
of T4 and T3. Brains were
removed, postfixed by immersion in the same fixative for 6 h, and
placed in 20% sucrose in PBS at 4 C overnight. Eighteen-micron coronal
tissue sections through the forebrain were obtained on a cryostat
(Reichert-Jung 2800 Frigocut-E, Leica, Deerfield, IL) and
adhered to SuperFrost Plus glass slides (Fisher Scientific International, Inc. Co., Pittsburgh, PA). The sections were
desiccated overnight by heating at 42 C and were stored at -80 C until
prepared for in situ hybridization histochemistry.
The hybridization protocol was based on methods previously reported from our laboratories (20). Tissue sections were hybridized with a single stranded [35S]UTP-labeled complementary RNA probe generated from a linearized 0.84-kb rat D3 (rD3) cDNA in pCR II (Invitrogen, San Diego, CA) vector containing a mutation in its coding region resulting in a cysteine codon in place of the TGA selenocysteine codon. The original rD3 cDNA was a gift from Dr. D. St. Germain (2). The plasmid was linearized using the XbaI site in the vector’s polylinker and transcribed with SP6 polymerase. The rD3 antisense probe contained the entire 833-nucleotide coding region and 5 nucleotides of the 3'-untranslated region. The same sequences were included in the sense RNA. Hybridization was performed under plastic coverslips in buffer containing 50% formamide, a 2-fold concentration of standard sodium citrate (2 x SSC), 10% dextran sulfate, 0.25% BSA, 0.25% Ficoll 400, 0.25% polyvinylpyrrolidone 360, 250 µM Tris (pH 7.5), 0.5% sodium pyrophosphate, 0.5% SDS, 250 µg/ml denatured salmon sperm DNA, and 6 x 105 cpm radiolabeled probe for 16 h at 55 C. Slides were dipped into Kodak NTB2 autoradiography emulsion (Eastman Kodak Co., Rochester, NY), and the autoradiograms were developed after 6 days of exposure at 4 C. After being cleared in graded solutions of ethanol and Histosol (National Diagnostics, Atlanta, GA), the sections were coverslipped in Histomount (National Diagnostics), and the autoradiograms were visualized and photographed under darkfield illumination with a Zeiss (Carl Zeiss Inc., Thornwood, NJ) or Olympus (Olympus America Inc., Lake Success, NY) binocular microscope. Some sections were counterstained with cresyl violet to determine whether silver grains were located in neurons as identified by their characteristic nuclear morphology.
RNA preparation and Northern analysis
Two series of studies of D3 mRNA expression were performed. The
first used total RNA prepared from euthyroid, hypothyroid, and
hyperthyroid rats, and the second poly(A)+ RNA from
euthyroid and hyperthyroid animals.
Animals were anesthetized with pentobarbital or CO2 and decapitated, and core blood was collected to confirm thyroid status by measurement of serum T4 by RIA. The brains were rapidly removed from the calvarium, and discrete regions were dissected under direct vision including the olfactory bulb, cerebellum, cerebral cortex, hippocampus, hypothalamus, midbrain, and pons. The cortex was removed by incising the brain along the rhinencephalic fissure and reflecting it off the hippocampus with a microspatula. The two lobes of the hippocampus were then divided from a dorsal approach with a scapula, and each lobe removed separately with a microforceps. The hypothalamus was removed as a cone from the base of the brain using the mamillary bodies, optic chiasm, and temporal lobes as boundaries. The cerebellum was removed after transecting the cerebellar peduncles. Surface landmarks were used to separate the midbrain from the pons, including the medial mamillary bodies and the superior colliculi. All tissues were snap-frozen in liquid nitrogen and stored at -80 C.
RNA was isolated according to the single step RNA isolation method of Chomczynski (22) by combining tissues from two or three identically treated animals. Total RNA was resuspended in 200–500 µl diethylpyrocarbonate-treated water and quantitated by spectrophotometer at 260- and 280-nm wavelengths. Poly(A)+ RNA was isolated from 300–900 µg total RNA from four to six animals for the various tissues with the PolyAT Tract mRNA Isolation System (Promega Corp., Madison, WI). Three to 10 µg poly(A)+ RNA were electrophoresed through 1% agarose-1.85% formaldehyde-0.5 µg/ml ethidium bromide-1 x MOPS (3-(N-morpholino)-propanesulfonic acid) at room temperature according to the procedure of Lehrach et al. (23). RNA was transferred by capillary action with 20 x SSC according to the manufacturer’s recommendation for the nylon membranes (GeneScreen Plus, New England Nuclear Life Sciences, Boston, MA), except that the gel was washed twice in 10 x SSC for 30 min each time at room temperature. The completion of transfer was verified by the presence of the 0.24- to 9.5-kb RNA mol wt marker bands (Life Technologies, Gaithersburg, MD) as well as the 28S and 18S ribosomal RNAs. RNA was fixed to the nylon membrane by UV cross-linking with the Stratalinker (Stratagene, La Jolla, CA).
Northern blots were hybridized with a rD3 cDNA under the stringency conditions of 5 x SSPE (180 mM sodium chloride, 10 mM sodium phosphate, 1 mM EDTA, pH 7.7), 5 x Denhardt’s solution, 0.5% (wt/vol) SDS, and 100 µg/ml denatured sonicated calf thymus DNA at 65 C. As a control for differences in loading and transfer, blots were stripped and reprobed with rat cyclophilin (rCYC; gift from W. W. Chin). For hybridization to the rD3 and rCYC probes, 1 x 106 and 0.5 x 106 cpm/ml, respectively, were applied to the blots and incubated for at least 16 h. Membranes were washed sequentially twice with 2 x SSPE-0.1% SDS for 10 min each time at room temperature; once with 1 x SSPE-0.1% SDS for 10 min at 42 C; once with 0.5% SSPE-0.1% SDS for 30 min at 42 C and for 30 min at 50 C; and once with 0.2 x SSPE-0.1% SDS for 30 min at 50, 55, and 60 C. For the probing with rCYC, the final wash was in 0.2 x SSPE-0.1% SDS for 1 h at 65 C. Between probings, the blots were stripped according to the manufacturer’s recommendations in 10 mM Tris-HCl (pH 7.5), 1 mM EDTA (pH 8.0), and 1% SDS and then autoradiographed to show that no residual signal was present. Blots were autoradiographed for at least 7 min at room temperature (rCYC) for 20 days at -80 C (rD3) with an intensifying screen.
cDNA probes were made by random priming of template DNA with
[
-32P]deoxy-CTP. An 843-bp
BamHI/HindIII fragment of rD3 containing a
selenocysteine to cysteine mutation subcloned into a pCRII vector
(Invitrogen) was used. This fragment contains no
5'-flanking region, 833 bp of coding region, and 5 bp of 3'-flanking
region including the stop codon. A 0.75-kb
KpnI/SacI fragment of rCYC cDNA in pBSKS vector
(Stratagene, La Jolla, CA) was used. This fragment contains the entire
coding region of the rCYC (24).
Quantitation of hybridization signals was performed with a scanning densitometer and Molecular Dynamics, Inc. software (version 3.1, Sunnyvale, CA). The D3 mRNA expression was normalized to the rCYC hybridization signal.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), but was particularly striking in
layers II–VI of the cerebral cortex, hippocampal pyramidal cells,
granule cells of the dentate, and layer II of the pyriform cortex
(
Figs. 1–3).
Localization of silver grains overlying neurons in the CA3 region of
the hippocampus was confirmed in sections counterstained with cresyl
violet (Fig. 4). Thyroidectomy resulted
in a general reduction in the accumulation of silver grains over all
hybridized structures in the forebrain (Figs. 2 and 3). In contrast,
T3 administration resulted in a marked increase
in D3 mRNA, particularly in the cerebral cortex and hippocampus (
Figs. 1–3). In the cerebellum, silver grains accumulated primarily over the
granule cell layer. Similar to other regions of the forebrain,
hypothyroidism tended to reduce D3 hybridization, whereas excess
T3 increased hybridization. In the hypothalamus,
moderate hybridization was observed throughout, with the exception of
the supraoptic nucleus, where in some hyperthyroid animals a higher
signal was observed.
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). There was insufficient
mRNA from the small pieces of hypothalamic tissue to obtain significant
quantities of mRNA. The 3.0-/3.3-kb doublet was easily seen on shorter
exposures. The same transcripts were present in much reduced amounts in
the cortex, hippocampus, and olfactory bulb of euthyroid animals. In
the cerebellum from normal rats, levels of the 2.6-kb transcript and
the doublet were barely detectable, and the 2.0-kb band was
undetectable.
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and 2). In the euthyroid animals, the 2.6-kb
transcript was the major transcript, but was barely detectable in the
cerebellum and olfactory bulb. The quantities of the different sized
transcripts in hyperthyroid rats varied between tissues, with the
2.0-kb mRNA predominant in the cerebellum and olfactory bulb and the
2.6-kb band predominant in the cortex and hippocampus of the
T3-treated animals (Table 1). Hyperthyroidism
caused a 4.4- to 53-fold increase in total D3 mRNA expression
(Table 2), with the cerebellum showing the greatest increase in
response. The increases in the quantities of the different sized
transcripts varied markedly from region to region, however. For
instance, T3 treatment resulted in a 2.9-fold
increase in the 2.6-kb mRNA in the olfactory bulb, but a 21-fold
increase in the cerebellum. Because of differences in loading (see CYC
expression), the high expression of D3 mRNA transcripts in the
olfactory bulb was not obvious on the Northern blot.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The areas in which D3 mRNA is highly expressed, including the pyramidal
cells of the hippocampus and layers II–VI of the cerebral cortex,
presumably are those in which T3 homeostasis can
be inferred to be most important. The presence of D3 mRNA in neurons in
these areas was confirmed by cresyl violet counterstains. Although it
is well recognized from studies of primary cultures that astrocytes and
oligodendroglia can express D3 activity, this is the first
documentation of D3 mRNA expression in neurons (19, 25, 26, 27). In this
regard, it is of interest that these regions also contain the highest
concentration of thyroid hormone receptors in the central nervous
system (28, 29) and have critical roles in learning, memory, and higher
cognitive functions (30). Although thyroid insufficiency clearly
impairs the proliferation, arborization, and synapse formation of
hippocampal and cerebral cortical neurons and can result in cretinism
and a variety of neurological manifestations (see Refs. 28, 31 for
discussion), excess thyroid hormone also can have adverse effects on
both the developing and the mature brain. For example, thyrotoxicosis
can increase neuronal excitability and induce epileptic seizures (32, 33), whereas the administration of excess T4 to
neonatal rats disrupts learning and memory in adults (34, 35). Along
these lines, hyperthyroidism can reduce the density of apical dendritic
spines in region CA1 of the hippocampus (36), stimulate aberrant mossy
fiber projections to region CA3 and the dentate (37), attenuate long
term potentiation induction (38), and down-regulate benzodiazepine and
-aminobutyric acid receptors in the cerebral cortex (39, 40),
possibly explaining some of the detrimental effects of excess thyroid
hormone on the hippocampus and cerebral cortex. Similarly, the
cerebellum is adversely affected by either insufficient or excess
thyroid hormone; the administration of high doses of
T4 to neonatal rats leads to abnormal development
of the cerebellum, manifested by a reduction in the total number of
granule cells (41) and a reduction in total synaptic profiles (42). It
is of interest, therefore, that the highest concentration of D3 mRNA
was identified in the granule cells. A precise homeostatic mechanism to
regulate the concentration of thyroid hormone in the brain, therefore,
may be essential to prevent potential destructive influences of excess
thyroid hormone on neurons and to reduce T3 and
T4 degradation in the hypothyroid state.
There are few data available with respect to expression of D3 mRNA in
mammalian tissues. Northern analyses illustrate that there are at least
four differently sized mRNAs in the rat central nervous system (Fig. 5
). Croteau et al. found that
the 1.6-, 3.3-, and 3.6-kb mRNAs were barely visible in 5–10 µg
poly(A)+ RNA from the cerebral cortex of euthyroid animals,
with the 3.3- and 3.6-kb transcripts increased in intensity in
hyperthyroid rats (2). Likewise, in our studies of human tissues, we
were unable to detect any bands specific to D3 in 2 µg
poly(A)+ RNA extracted from total cerebral cortex despite
the fact that D3 activity is present in the human central nervous
system (6, 10). Of the tissues examined by in situ
hybridization studies, the hippocampus showed the highest ratio of
D3/CYC on Northern analysis.
The increase in D3 mRNA after a short term T3 treatment was dramatic. At this time it is not possible to determine whether this reflects T3-induced increases in gene transcription, mRNA stabilization, or a combination of these. Qualitatively, the pattern of mRNA transcript expression in the hyperthyroid state is similar in the cortex and hippocampus, on the one hand, and the cerebellum and olfactory bulb, on the other. In the cortex and hippocampus, the 2.6-kb mRNA is predominant, whereas in the cerebellum and olfactory bulb, the major band is 2.0 kb in size. In the cortex and hippocampus, T3 treatment increased the 3.0-/3.3-kb and 2.0-kb mRNA by the largest amount, whereas in the cerebellum and olfactory bulb, the greatest increase was in the 2.0-kb band. As traces of the larger bands were present in euthyroid cortex and hippocampus, their prominence after T3 treatment could simply reflect an increase in the D3 mRNA induced by hyperthyroidism. On the other hand, in the euthyroid state, the 2-kb transcript was barely detectable. In the hyperthyroid animals, transcripts of the same size as those in the hippocampus appear in the cerebellum and olfactory bulb, suggesting again that the different transcripts represent a quantitative, rather than a qualitative, change. We could not identify D3 mRNA in hypothalamic extracts, suggesting that it is expressed at low levels in this tissue. By in situ hybridization histochemistry, we detected only modest quantities of D3 mRNA in the hypothalamus with accumulations in the supraoptic nucleus only in some hyperthyroid animals. Low levels of D3 activity have been previously reported in hypothalamic tissue, consistent with these results. As there is no information available on the structure of the rat D3 gene, it is not known whether the differences in transcript sizes are due to alternative splicing, differences in polyadenylation, and/or the use of different poly(A) addition signals.
Although it is difficult to provide precise quantitative information due to the low levels of D3 mRNA in the euthyroid brain, hyperthyroidism causes a 4- to 50-fold increase in D3 expression in these four subfractions of the central nervous system. In addition to the above-mentioned studies of Kaplan et al. (12, 13, 14), T3 responsiveness of D3 activity has been demonstrated in several tissues of R. catesbeiana and X. laevis tadpoles (8, 9). However, D3 activity does not increase in the placenta of the hyperthyroid rat, indicating that the same gene is differentially responsive to thyroid hormone in different tissues (43, 44). That such marked increases in D3 mRNA should occur is all the more remarkable given the fact that T3 receptors are nearly saturated in the cerebral cortex of the euthyroid rat due to the substantial contributions to nuclear receptor T3 of locally produced T3 derived from the action of D2 (45, 46, 47, 48).
Although it seems physiologically appropriate that D3 activity should increase in the hyperthyroid state and decrease during hypothyroidism to maintain T3 homeostasis in the central nervous system, D3 may also have an important role during iodine deficiency. Iodine deficiency, a significant stress to the thyroid economy of all vertebrates, has also been shown to be associated with a decrease in D3 activity as well as an increase in that of D2 (49). This indicates that in the central nervous system, increases in D2 combined with compensatory decreases in D3 activity, such as those found in the hypothyroid state, are an integral component of the response of the brain to the challenge of iodine deficiency (15, 16). The present in situ results show that D3 mRNA is diffusely expressed throughout the central nervous system, although it is particularly concentrated in the pyramidal cells of the hippocampus and cerebral cortex. These results suggest that the entire central nervous system, and these regions in particular, are highly sensitive to intracellular T3 concentrations, and that potent strategies have evolved to maintain T3 constant when T4 production is impaired.
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Footnotes |
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Received May 29, 1998.
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References |
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1-, 2-, ß,
imipramine and GABA receptors in the rat brain. Life Sci 48:659–666[CrossRef][Medline]
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W. W. Li, C. Le Goascogne, M. Ramauge, M. Schumacher, M. Pierre, and F. Courtin Induction of Type 3 Iodothyronine Deiodinase by Nerve Injury in the Rat Peripheral Nervous System Endocrinology, December 1, 2001; 142(12): 5190 - 5197. [Abstract] [Full Text] [PDF]
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R. Peeters, C. Fekete, C. Goncalves, G. Legradi, H. M. Tu, J. W. Harney, A. C. Bianco, R. M. Lechan, and P. R. Larsen Regional physiological adaptation of the central nervous system deiodinases to iodine deficiency Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E54 - E61. [Abstract] [Full Text] [PDF]
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V. A. Galton, E. Martinez, A. Hernandez, E. A. St. Germain, J. M. Bates, and D. L. St. Germain The Type 2 Iodothyronine Deiodinase Is Expressed in the Rat Uterus and Induced During Pregnancy Endocrinology, May 1, 2001; 142(5): 2123 - 2128. [Abstract] [Full Text]
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M. Eravci, G. Pinna, H. Meinhold, and A. Baumgartner Effects of Pharmacological and Nonpharmacological Treatments on Thyroid Hormone Metabolism and Concentrations in Rat Brain Endocrinology, March 1, 2000; 141(3): 1027 - 1040. [Abstract] [Full Text] [PDF]
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