Endocrinology Vol. 138, No. 10 4248-4254
Copyright © 1997 by The Endocrine Society
Mammary Gland Type I Iodothyronine Deiodinase Is Encoded by a Short Messenger Ribonucleic Acid1
Luz Navarro,
Abraham Landa,
Carlos Valverde-R and
Carmen Aceves
Departamento de Neuroendocrinología, Centro de
Neurobiología, Campus Juriquilla Queretaro,y Departmento de
Microbiología y Parasitología, Facultad de Medicina,
Mexico, D. F.,Universidad Nacional Autonoma de Mexico, Mexico
Address all correspondence and requests for reprints to: Dr. Luz Navarro, Centro de Neurobiologia, Universidad Nacional Autonoma de Mexico, Apartado Postal 1–1141, Queretaro 76001, Qro. Mexico. E-mail:
lnavarro{at}servidor.unam.mx
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Abstract
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Lactating rat mammary gland expresses a deiodinating activity that, on
the basis of kinetic characteristics, corresponds to the so-called
5'-deiodinase type I (D1). In the present study we amplified and
sequenced several D1 complementary DNA (cDNA) fragments from rat
lactating mammary gland. The mammary cDNA was found to be identical to
the previously reported rat liver cDNA in the coding region, but 465
nucleotides shorter on its 3'-untranslated region, suggesting that the
D1 is the same in both tissues. D1 messenger RNA (mRNA) was also
detected by reverse transcriptase-PCR in mammary glands from puberal
and late pregnant rats, but not in virgin animals. Densitometric
analysis showed a close and direct correlation between mRNA content and
enzyme specific activity in mammary gland. Our results also show that
rat liver contains both D1 mRNA forms and that the large form may
respond to the thyroid status. These data suggest a differential and
organ-specific expression of these mRNA forms, which could play a role
in the functional regulation of D1 activity.
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Introduction
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THE PERIPHERAL conversion of
T4 to T3 or
rT3 is catalyzed by a group of enzymes known as
iodothyronine deiodinases (1). All members of this family contain the
uncommon amino acid selenocysteine (Se-Cys) at their active sites
(2, 3, 4). Type I deiodinase (D1) is a microsomal protein of approximately
29 kDa that, depending on the sulfation state of its substrate, is able
to deiodinate either the phenolic or the tyrosyl ring of
T4 and other iodothyronines. D1 activity is
sensitive to inhibition by propylthiouracil (PTU) or gold thioglucose,
a property that is useful in distinguishing this activity from the rest
of deiodinases. (5). This enzyme is expressed predominantly in the
liver, kidney, and thyroid gland, but it is also detected in other
organs, such as heart, anterior pituitary gland, and lactating mammary
gland (5, 6). Within the past few years several studies have provided
convincing evidence showing that lactation is accompanied by a
characteristic euthyroid sick-like syndrome and opposite changes in
mammary gland and liver deiodinase activity. As lactation progresses
there is a clear-cut increase in this enzyme activity in the mammary
gland (6, 7) and a concomitant decrease in the liver (7, 8, 9).
Furthermore, the kinetic characterization of this enzymatic activity in
rat lactating mammary gland has revealed that it corresponds to D1 (6, 10, 11). Rat mammary D1 activity during lactation is only about 0.5%
of that observed in the liver (11, 12) and exhibits a significant
increase in the presence of specific stimuli, such as lactation
intensity (7, 13) or overfeeding (14). However, recently, Jack et
al. (12) were unable to detect D1 messenger RNA (mRNA) in the rat
lactating mammary gland using Northern analysis and a reverse
transcriptase-PCR assay (RT-PCR). The researchers suggested that the D1
in lactating mammary gland could be encoded by a different mRNA (12).
In this context, sequence analysis of several D1 complementary DNAs
(cDNAs) have revealed that the enzyme is highly homologous in all
species studied (2, 15, 16, 17). However, a detailed analysis of these data
suggest that D1 seems to be encoded by at least two forms of mRNA.
Thus, Berry et al. (2) described a mRNA of 2094 bp in the
rat liver with two potential polyadenylation signal sites (the first at
1612 bp and the second at 2069 bp); this clone was designated G21.
Recently, hepatic D1 mRNAs for the dog (15), mouse (16), and human (17)
have been described. Dog and mouse messengers exhibit 76–86% homology
compared with G21, both contain only the first polyadenylation signal
and end at approximately 1600 bp, thus being about 450 bp shorter than
G21 on the 3'-untranslated region (3'UTR). In the case of the human,
only one sequence has been described and is incomplete because the
polyadenylated [poly(A)] tail was not found (17). However, as in the
case of rat and mouse, the reported human sequence also contains a
polyadenylation signal close to and downstream of the selenocysteine
insertion sequence (SECIS) region (1825 bp). The physiological
importance of these different transcripts has not been elucidated.
However, several studies on other transcripts have demonstrated that
the 3'UTR is involved in the control of stability of mRNA and
represents a site of functional regulation (18, 19, 20, 21).
The present study was undertaken with the aim to reevaluate the
presence of D1 mRNA in lactating rat mammary gland. To this end, a set
of specific primers to G21 were used in the RT reaction of the RT-PCR
procedure, thus increasing the probability of identifying D1 mRNA(s).
The results strongly suggest that 1) lactating mammary gland D1 is
identical to that expressed in the rat liver, but is encoded by a
shorter mRNA form; 2) during the breeding cycle, there is a close and
direct correlation between mRNA content and enzyme specific activity in
mammary gland, suggesting that this enzyme is regulated predominantly
by pretranslational mechanisms; 3) rat liver D1 is encoded by two
messengers that differ in the length of their 3'UTR; and 4) the large
mRNA form that corresponds to G21 increases during hyperthyroidism and
decreases during hypothyroidism and lactation. Together, these data
show a differential and organ-specific expression of D1 mRNA forms,
which suggests that they may play a role in the functional regulation
of this enzyme.
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Materials and Methods
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Animals
Sprague-Dawley rats were obtained from Charles River Breeding
Laboratories (Burlington, MA) and kept under conditions of controlled
lighting (12 h of light, 12 h of darkness) and temperature. Food
and water were available ad libitum. The animals used in
this study were adult male euthyroid (7 weeks old), hypothyroid
(thyroidectomized 3 weeks before killing), hypothyroid and
T4 replaced (daily sc injections of 1.5 µg of
T4/100 BW for 8 days before killing), hyperthyroid (daily
sc injections of 20 µg T4/100 BW for 8 days before
killing), female puberal (4 weeks old), virgin (7 weeks old), 14-day
pregnant, and lactating (1- and 10-day postpartum) with litter adjusted
to 10 pups each. Animals were killed by decapitation, and tissues were
immediately dissected, homogenized, and processed for RNA extraction or
deiodinase activity determination.
5'-Deiodinase assay
D1 activity was determined using a modification of the methods
previously described (22) and characterized for mammary gland (7). In
brief, tissues were homogenized in ice-cold 0.32 M sucrose,
10 mM HEPES (pH 7), 5 mM dithiothreitol, and 1
mM EDTA and centrifuged at 1000 x g at 4
C. The reaction mixture containing 5 µg (liver) or 200 µg (mammary
gland) supernatant protein, and 0.5 µM of an isotopic
solution of [125I]rT3 (New England
Nuclear, Boston, MA; SA, 1250 µCi/µg) and 5 mM
dithiothreitol. The assay was carried out with and without 1
mM PTU. Incubations were performed at 37 C for 1 h
(liver) or 3 h (mammary gland). The released acid-soluble
radioiodide was isolated by chromatography on Dowex 50W-X2 columns.
Proteins were measured by the Bradford method (Bio-Rad protein assay,
Bio-Rad, Richmond, CA). Results are expressed as picomoles of
radioiodide released per mg protein/h.
Northern blot analysis
Total RNA was extracted using a modification of the Chirgwin
method as previously described (23). Poly(A) RNA was isolated from
total RNA using an oligo(deoxythymidine)-cellulose
[oligo(dT)-cellulose] column. Northern blot analysis was performed
using 5 µg poly(A) RNA from liver or mammary glands. Two different
stringency conditions were used in the hybridization; low [6 x
SSC (standard saline citrate), 5 x Denhardt’s, 0.5% SDS, and
100 µg/ml salmon sperm DNA; overnight at 55 C; washes in 0.1 x
SSC and 0.1% SDS at room temperature and at 55 C] and high [5
x SSC, 5 x Denhardt’s, 0.1 M phosphate buffer (pH
6.5), 100 µg/ml salmon sperm DNA, and 50% formamide; washes in
0.1 x SSC and 0.1% SDS at room temperature and at 42 C]. The
G21 D1 cDNA, provided by Drs. M. Berry and P. R. Larsen (Brigham
and Women’s Hospital, Boston, MA), was used as a probe in these
studies.
RT-PCR assays
Oligonucleotide primers used in the RT-PCR assays are shown in
Table 1
and were derived from the
sequence of G21. Primers were synthesized by Life Technologies (Grand
Island, NY). To detect and amplify the coding region from
G21-associated transcripts, 2 µg lactating mammary gland or liver
total RNA were reverse transcribed using a Superscript RT (Life
Technologies) and a specific D1 antisense oligonucleotide primer
(M7as). PCR was then carried out on a 5-µl aliquot of the RT reaction
mixture, using oligonucleotide primers M1s and M6as. Other components
of the PCR mixture included 2.5 pmol of each oligonucleotide primer,
200 µM deoxy-NTPs, and 2.5 U Taq polymerase
(Promega) in a 50-µl total volume reaction. Amplification was carried
out for 32 cycles of 94 C for 45 sec, 54 C for 45 sec, and 72 C for 1
min. Amplified fragments were electrophoresed on 1% agarose gel,
transferred to a nylon membrane, and then hybridized with a nested
radiolabeled oligonucleotide probe (M4s). Similar methods were used to
detect and amplify the 3'-region of G21-associated transcripts, except
that J1as oligonucleotide was used in the RT reaction, and
oligonucleotides M2s and J2as were used as primers in the PCR
amplification. Southern blotting of these amplicons was performed using
the nested J3s oligonucleotide as a probe. Mixture containing a RNA
sample and the appropriate oligonucleotide primers, but without the RT,
was used as control. RT-PCR assay was also used to analyze the presence
of D1 mRNA in mammary gland during the different stages of the breeding
cycle. M7as oligonucleotide was used for the RT reaction. PCR was
carried out on a 5-µl (mammary glands) or a 1-µl (liver) aliquot of
the reverse transcription with M2s-M6as oligonucleotides. Radiolabeled
M4s oligonucleotide was used for Southern blotting. Densitometric
analysis was performed in a PhosphorImager analyzer (Molecular
Dynamics, Sunnyvale, CA).
Amplification of the 3'UTR
The length of the 3'UTR D1 mRNA was assessed using 2 µg total
RNA from liver or 10-day lactating mammary gland and a rapid
amplification of 3'-DNA ends (3'-RACE) procedure (Life Technologies) as
previously described (4). Oligo(dT) with a terminal-specific sequence
(AP oligonucleotide; see Table 1
) was used for the RT reactions. PCR
amplification was carried out with the complementary terminal sequence
of oligo(dT) denoted universal amplification sequence or UAP and J2s
for 32 cycles. To verify the presence of the long form of D1 mRNA in
both tissues, a PCR amplification was carried out with As and Bas
oligonucleotides, the sequences of which are present only in the long
mRNA form. PCR reactions contain the standard mixture and a 1-µl
(liver) or a 5-µl (mammary gland) aliquot from the previous RT
reaction.
Sequence analysis
The amplified fragments (see Fig. 4) were sequenced by an
automated sequence system that uses the PRISM Ready Reaction Dye Deoxy
Terminator Cycle Sequencing Kit (Applied Biosystems, Foster City,
CA).
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Figure 4. RT-PCR amplification strategy for mammary gland D1
transcript. Schematic representation of the rat liver D1 cDNA derived
from the published sequence (2). The solid bar
corresponds to the coding region. The open bars
correspond to the 5'- and 3'UTRs. The amplified fragments are shown as
discontinuous lines with the oligonucleotides used for
the PCR. The oligonucleotide used for the RT reaction are shown within
parentheses. Arrows below each fragment
indicate the direction and length of the region sequenced.
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Statistical analysis
All values are expressed as the mean ± SEM.
Differences between groups were analyzed by one-way ANOVA and Tukey’s
test or Kruskal-Wallis one-way ANOVA. P < 0.05 was
considered statistically significant.
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Results
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Figure 1 shows that at lower
stringency (A), lactating mammary gland poly(A) RNA yields a
hybridizing band smaller than that from the liver (1.6 vs.
2.1 kilobases, respectively). However, this signal disappears under
high stringency conditions (Fig. 1B). Similar results were obtained
when using mammary gland total RNA and Northern or slot blot (data not
shown).
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Figure 1. Northern blot analysis of D1 mRNA. Poly(A) RNA (5
µg/lane) was extracted from liver of hyperthyroid and euthyroid male
rats and from mammary glands of 12-day pregnant female (G-12 M.G.) and
10-day lactating female (L-10 M.G.). A, At low stringency; B, at high
stringency.
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To confirm the presence of D1 mRNAs in the lactating mammary tissue,
in vitro amplifications by RT-PCR were performed. As
expected, using mammary total RNA and primers M1s and M6as, a 561-bp
DNA fragment was amplified (Fig. 2). A
longer DNA fragment (1116 bp) was obtained by using primers M2s and
J2as (data not shown). To verify that the D1 gene expression is not a
ubiquitous phenomenon in the mammary gland, similar experiments were
carried out using total RNA from male rat liver and mammary gland from
12-day pregnant rats. DNA fragments of the predicted size were
amplified only from liver and lactating mammary gland, but not from
12-day pregnant mammary gland.
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Figure 2. Amplification of the mammary gland mRNA 5'-region.
We used M7as primer for RT reaction. PCR was carried out on a 5-µl
(mammary glands) or 1-µl (liver) aliquot of the reverse transcription
with M1s-M6as oligonucleotides. Lanes 1 and 2 correspond to euthyroid
liver, with (RT+) and without (RT-) RT, respectively. Lanes 3 and 4,
Twelve-day pregnant mammary gland (RT+ and RT-, respectively). Lanes 5
and 6, Ten-day lactating mammary gland (RT+ and RT-, respectively);
lane 7, control (H20 with all the reagents). A, Gel stained with
ethidium bromide. B, Southern blotting of the RT-PCR products.
Hybridization was carried with labeled M4as oligonucleotide.
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The PCR-RACE method was employed to analyze the 3'-terminal region D1
mRNA from liver and mammary gland, using oligonucleotide AP for the RT
reaction, and J2s and UAP for the PCR amplification. Figure 3A shows that two fragments were
amplified from liver cDNA, one of the expected size (617 bp) and
another of 150 bp, indicating the presence of two D1-mRNA forms.
The large fragment is more abundant in hyperthyroid rat liver and
practically disappears in liver from hypothyroid and lactating animals.
Furthermore, the large fragment is restored in T4-replaced
hypothyroid animals. In contrast, the short fragment remains unchanged.
On the other hand, just one short fragment of 150 bp was amplified
using cDNA from lactating mammary gland, thus indicating that this
tissue only presents the short D1 mRNA form. To corroborate these
results, we carried out a PCR amplification using oligonucleotides As
and Bas, which only amplify cDNAs corresponding to the long D1 mRNA
form. Fragments of the expected size (136 pb) were amplified from
livers, and no amplification was obtained from mammary gland (Fig. 3B).
These data confirm that the long D1 mRNA form present in liver is
modified by the thyroid status and is absent in mammary gland. Figure 3A also shows a more intense signal for the short fragment than for the
larger one, suggesting that the short mRNA is more abundant.
Nevertheless, it is difficult to interpret the relative quantities of
the two isoforms considering that a coamplification took place, and the
replication efficiency is dependent on the fragment size (24).
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Figure 3. PCR-RACE amplification of 3'UTR of D1 mRNAs.
Oligo(dT) with a specific sequence denoted AP (see Table I and
Materials and Methods) was used for the RT reactions. In
A, PCR was carried out with the complementary sequence oligo(dT), UAP,
and J2s. Southern blotting was performed using the nested J1AS
oligonucleotide as a probe. In B, PCR was carried out with
oligonucleotides As and Bas, and radiolabeled As was used for Southern
blotting. PCR amplifications were carried out on 1-µl (livers) or
5-µl (mammary glands) aliquots of the RT reaction. Lanes are as
follows: eu, euthyroid male liver; hyper, hyperthyroid male liver; Tx,
hypothyroid male liver; Tx+T4: replaced T4
hypothyroid male liver; eu, euthyroid female liver; lactating,
lactating female liver; mammary gland; RT-, euthyroid male liver
without RT and H2O with all the reagents.
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The nucleotide sequences of amplified fragments from lactating mammary
gland were determined (Fig. 4) and
compared with the sequence of G21 (Fig. 5). All fragments showed sequences
identical with that of G21 except for 15 residues on the 3'UTR. These
data strongly suggest that both tissues express identical D1. However,
the mammary gland mRNA is 
450 bp shorter in the 3'UTR, suggesting
that it ends at the first polyadenylation signal. We also amplified and
sequenced fragments obtained from the hepatic short mRNA form, and the
sequence was identical to the sequence from G21 (data not shown).
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Figure 5. Nucleotide sequence comparison of D1 cDNAs from
liver (G21) and lactating mammary gland (MG) in the rat. The alignment
of nucleotide sequences refers to the liver cDNA sequence (2).
Dashes indicate nucleotides identical to those of the
reference sequence. The initiator ATG and stop TAG codons and the two
polyadenylation signals are in bold fonts; the TGA
selenocysteine codon and SECIS element are underlined.
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To explore the physiological regulation of the D1 gene in the mammary
gland, D1 mRNA was examined in female rats during the breeding cycle
and compared with the specific enzymatic activity (Fig. 6). D1 transcript levels were determined
using a RT-PCR assay and mammary gland total RNA extracted from
puberal, virgin, pregnant, and lactating rats. PCR products generated
using primers M2s and M6as showed that D1 mRNA is present in puberal,
14-day pregnant, and 1- and 10-day lactating animals. The data also
show that there was a direct correlation between the amount of
amplified fragments and the specific enzyme activity.
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Figure 6. Comparison between D1 enzymatic activity and mRNA
content in mammary glands during the breeding cycle. A, Enzymatic
activity. B, Densitometric units (PhosphorImager analyzer) of the
Southern analysis for D1 RT-PCR fragments shown in C. M7as
oligonucleotide was used for the RT reaction. PCR was carried out on a
5-µl (mammary glands) or a 1-µl (liver) aliquot of the reverse
transcription with M2s-M6as oligonucleotides. Radiolabeled M4s
oligonucleotide was used for Southern blotting. ML, Male liver; P,
puber; V, virgin; G-14, 14 days of pregnancy; L-1, 1 day of lactation;
L-10, 10 days of lactation. Values are presented as the mean ±
SEM (n = 3). Means with different letters are
significantly different [by one-way ANOVA and Tukey’s HSD test
(capital letters) or Kruskall-Wallis test (small
letters)].
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Discussion
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A short form of D1 mRNA in lactating rat mammary gland was
identified by using a modified RT-PCR analysis that allows the
identification of scarce or not abundant transcripts. Indeed,
densitometry approximations revealed that the lactating mammary gland
contains about 200 times less D1 mRNA than the liver. These findings
are consonant with our failure to detect this mRNA by direct methods
such as Northern or slot blot analyses. There is an apparent
controversy between our present results and the unsuccessful efforts by
Jack et al. (12) to identify this messenger using random
hexanucleotides as primers for the RT reaction and a competitive PCR.
However, a plausible explanation could be that these researchers used a
shorter internal control for their competitive PCR than the expected
fragment. It is known that when two DNA fragments are coamplified, the
longer fragment experiences a decrease in its replication efficiency
before the shorter one does (24).
Mammary D1 cDNA sequencing revealed that despite being 465 bp shorter
than G21, its coding region is identical to the corresponding region of
the hepatic clone. Furthermore, in both cDNAs, the SECIS region is
present in the same position. This finding indicates that the D1
expressed in the rat lactating mammary gland and liver are identical
and is consistent with previous studies showing that in operational
terms (Km, preferential substrate, PTU
sensitivity, etc.), mammary deiodinase activity corresponds
to a D1 (6, 10, 11). Similarly, the demonstration of a close and direct
correlation between mammary D1 mRNA content and specific deiodinase
activity in the breeding cycle allows us to propose the involvement of
pretranslational mechanisms in their regulation. This agrees with
previous studies indicating that mammary D1 is confined to the alveolar
epithelium (11) and that it is suckling stimulus dependent (25).
The present findings also demonstrate that rat liver contains two
different D1 mRNA forms that differ in their lengths at the 3'UTR. The
size of the short D1 mRNA as well as that of the mammary D1 mRNA (1630
bp) closely correspond to the use of the first polyadenylation signal
site contained in G21. Although the length of the long form corresponds
to the expected size throughout the use of the second polyadenylation
signal site also present in G21. Several studies have demonstrated that
the 3'UTR represents a site of functional regulation in mRNA stability
(18, 19, 20, 21). In particular, the presence of an AUUUA motif between two
polyadenylation signals, as in the case of G21, has been associated
with the translation-dependent instability of mRNA encoding for other
transcripts (20, 21). The mechanisms involved in the alternative
election between polyadenylation signal sites are practically unknown
and constitute an exciting new field in understanding the control of
mRNA translation (19). Data obtained from this work not only confirm
that thyroid hormones regulate liver D1 mRNA expression (26), but also
suggest that they could form some of the factors that regulate the
differential expression of D1 mRNA forms. Thus, although thyroid status
has no evident effect on the hepatic short messenger, we here show that
the large form increases in hyperthyroidism and decreases in
hypothyroidism. These findings and the well documented euthyroid
sick-like syndrome that characterizes lactation (7, 8, 9) could also
explain the decrease in the long D1 mRNA form observed in lactating rat
liver. Similarly, the data presented here are in agreement with the
differential D1 response that occurs in the liver, kidney, and thyroid
gland during hyperthyroidism (27, 28, 29), TSH administration (30), and/or
selenium depletion (31). Thus, despite the fact that there is no
available information concerning which mRNA forms are expressed in
kidney or thyroid gland, the present results suggest that not only
thyroid hormones, but TSH and selenium as well, may exert a
differential and organ-specific regulation of the expression of these
D1 mRNA forms. Furthermore, this differential response is consonant
with the fact that G21 corresponds to the large mRNA form and was
isolated from hyperthyroid male rats (2), whereas the short D1 mRNA
forms described in the dog and mouse arose from euthyroid animals (15, 16). Moreover, the presence of two thyroid hormone response elements in
the human Dio1 gene that have not been identified in the mouse (32)
suggests a possible species-specific regulation or the existence of
more than one D1 gene. However, further studies will be required to
analyze the possible differences in translational efficiencies and/or
stability of these messenger forms as well as the influence that
factors such as TSH, selenium, or iodine may exert on their
regulation.
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Acknowledgments
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We thank Dr. Galton’s laboratory at Dartmouth College,
especially Jennifer Davey for their helpful advice with the molecular
biology techniques. We also thank Aurea Orozco for her critical review
of this paper.
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Footnotes
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1 This work was supported in part by Grants DGAPA-UNAM IN203492 and
IN206496 as well as NIH-Fogarty Award TWO5215–01. 
Received February 5, 1997.
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Abstract
Introduction
