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T1 Cells1
Departments of Reproductive Medicine and Neurosciences and the Center for Molecular Genetics, University of California-San Diego (B.Y., E.T.A., P.L.M.), La Jolla, California 92093-0674; and the Department of Medicine, University of Colorado Health Sciences Center (D.F.G., E.C.R.), Denver, Colorado 80262
Address all correspondence and requests for reprints to: Pamela L. Mellon, Ph.D., Department of Reproductive Medicine 0674, 2057 CMM-E, University of California-San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}uscd.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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T1, that
expresses thyrotrope-specific markers, overcomes these limitations.
However, because it was not possible to distinguish whether the tumor
from which the TT1 cells are derived originated in the pars distalis
or the pars tuberalis, it was necessary to define their cellular origin
and thereby establish their status as representative thyrotrope cells
for future molecular studies. In this study, we demonstrate that the
TT1 cells express thyroid hormone receptors (ß1 and ß2) and
their heterodimeric partner, retinoid X receptor-
. Treatment with
T3 causes a dose- and time-dependent decrease in the
expression of the TSH ß-subunit messenger RNA. In contrast to
previous reports in rat pituitary cultures, T3 does not
alter TSH ß-subunit messenger RNA stability in the TT1 cells.
Based on these data and the presence of thyrotrope-specific isoforms of
the transcription factor Pit-1, we conclude that the TT1 cells
represent differentiated thyrotropes of the pars distalis and will be a
useful model system for future analysis of the cis- and
trans-acting factors necessary for thyrotrope-specific
and thyroid hormone-regulated TSH gene expression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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TSH is a member of the glycoprotein hormone family and consists of two
subunits, and ß, that are encoded by distinct genes on different
chromosomes (1). The -subunit is shared by all members of the
glycoprotein hormone family, including LH, FSH, and CG, in addition to
TSH. The -subunit gene is, therefore, expressed in three discrete
cell types: the thyrotrope and gonadotrope cells of the anterior
pituitary and the trophoblast cells of the placenta. In contrast,
expression of the ß-subunit of TSH is restricted to the thyrotrope
cells. The cell type specificity exhibited by the ß-subunit of TSH as
well as the ß-subunits of the other glycoprotein hormones is
particularly relevant because it is the ß-subunit that confers
biological specificity to the mature hormone (2). It is the expression
of the TSH ß-subunit that anatomically defines the thyrotrope cell
and dictates TSH biological function.
The ontogeny of the thyrotrope population in the anterior pituitary has been deduced from a combination of morphological data obtained in normal and mutant animals. Lin et al. (3) proposed that two separate populations arise in the pituitary that differ in their requirement for the transcription factor Pit-1 for survival and are designated Pit-1-independent and Pit-1-dependent thyrotropes. Pit-1-independent thyrotropes are reported to be a transient population that exists only in the fetal pituitary, whereas the Pit-1-dependent population exists in both the fetal and the adult pituitary. This hypothesis has recently been disputed by evidence that a Pit-1-independent population exists in the adult pituitary of sheep as a component of the pars tuberalis (4). Pars tuberalis thyrotropes have also been described in the rat (5) and hamster (6). These thyrotrope cells of the pars tuberalis express the ß-subunit of TSH in the absence of the transcription factor, Pit-1 (3), and are not responsive to classical hypophyseal/thyroid feedback regulation (7). The existence of multiple thyrotrope cells in the pituitary whose TSH subunit genes are regulated by different mechanisms emphasizes the need to recognize the contributions of such minority cell populations both in vivo and in vitro.
The study of TSH gene regulation has depended heavily on the use of
heterogeneous model systems, including dispersed pituitary cells and
TtT-97 thyrotropic tumor cells (8, 9, 10, 11, 12). Alternatively, investigators
have used GH3 cells, a somatolactotrope cell line that does
not express endogenous TSH subunits but that permits a low level of
TSHß gene promoter activity in transient transfection assays
(13, 14, 15). Although these systems have been useful in identifying
multiple cis-acting elements involved in TSH gene
regulation, because of the multicellular makeup of dispersed
pituitaries or the nonthyrotropic origin of GH3 cells,
their usefulness for more detailed mechanistic studies is limited.
Additionally, although the TtT-97 thyrotropic tumor behaves in many
important ways like a normal thyrotrope cell, it is difficult to grow
and maintain, requiring 6 months for growth in a single animal before
investigations can be performed. We recently created a unique mouse
thyrotrope cell line (TT1 cells) by targeted tumorigenesis in
transgenic mice that expresses both the - and ß-subunits of TSH
(16). These cells represent the only clonal, fully differentiated,
mouse thyrotrope cell line available and are advantageous tools for
molecular and biochemical analysis. However, in light of the mixed
thyrotrope population in the pituitary, it was important to establish
whether they represent pars distalis or pars tuberalis thyrotropes. In
this report we have examined the TT1 cells for expression of Pit-1
isoforms associated with the pituitary and specifically the thyrotrope
population. In addition, to test whether these cells retain normal
responsiveness to endocrine feedback regulation, we tested these cells
for functional thyroid hormone receptors (TRs). Our results indicate
that the TT1 cells are derived from the pars distalis, as TSH
ß-subunit expression is negatively regulated by thyroid hormone in a
dose- and time-dependent manner. The TT1 cells, therefore, represent
a novel model system suitable for mapping previously unidentified
cis-acting DNA elements and trans-acting factors
involved in basal and hormonally regulated gene expression in pars
distalis thyrotropes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T1
cells were seeded on Matrigel-coated plates (Collaborative
Research, Bedford, MA), which facilitated adhesion. Matrigel was
diluted 30-fold with DMEM before coating the plates and allowed to dry
before plating cells. The cells were maintained at 37 C in an
environment of 5% CO2. Replacement with DMEM containing
10% FCS depleted of thyroid hormone by treatment with AG1X-8 resin
(Bio-Rad Laboratories, Inc., Richmond, CA) (17) was
performed 48 h before experiments. L-T3 (T3) and 5,6-dichloro-1-ß-ribofuranosyl benzimidazole (DRB) were purchased from Sigma Chemical Co.
Northern analysis
Total RNA was isolated by the method of Chomczynski and Sacchi
(18), and 10 µg of each sample were electrophoresed in a 1% agarose
gel containing formaldehyde. After transfer onto nylon membrane
(GeneScreen, New England Nuclear, Boston, MA), the RNA was UV
cross-linked using a Bio-Rad UV chamber (Bio-Rad Laboratories,
Inc., Richmond, CA). After prehybridization, membranes were
hybridized with a 32P-labeled complementary DNA (cDNA)
probe overnight at 55 C in a 25% formamide solution.
32P-Labeled DNA were generated by random priming (19, 20)
from cDNA fragments of mouse TSH ß-subunit (21), mouse -subunit
(22), and mouse glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (23).
Excess probe was removed by washing at 65 C with 0.2 x SSPE (36
mM NaCl, 2 mM sodium phosphate, and 0.2
mM EDTA) and 0.1% SDS. Blots were stripped by boiling in
1% glycerol, 0.5% SDS, and 2 mM EDTA before
rehybridization with subsequent probes. Quantification of the
transcript levels was performed using a phosphor imaging system and
ImageQuant software (Molecular Dynamics, Inc., Sunnyvale,
CA). TSH ß-subunit and -subunit messenger RNA (mRNA) values were
normalized to GAPDH mRNA levels in the same lane to correct for loading
differences.
For the Northern blots to detect mouse retinoid X receptor- (RXR)
(24) and TRß1 (10) transcripts, 20 µg total RNA or 8 µg
polyadenylated [poly(A)+] RNA were denatured and
electrophoresed through 0.8% agarose gels containing 6.6%
formaldehyde, transferred to Nytran filters (Schleicher and Schuell,
Keene, NH), then hybridized overnight with 32P-labeled
mouse cDNA probes at 42 C in 50% formamide, 1 M NaCl, 10
mM sodium phosphate (pH 7), 0.1% sodium pyrophosphate,
5 x Denhardt’s solution, 1% sodium lauryl sulfate, and 0.25
mg/ml denatured salmon sperm DNA. Filters were then washed at 60 C with
0.2 x SSC (30 mM NaCl and 3 mM sodium
citrate, pH 7) and 0.1% SDS, followed by autoradiographic exposures of
16–40 h at -70 C.
Detection of Pit-1 isoform transcripts
RT-PCR was used to detect isoforms of Pit-1, as described
previously (12). The strategy is depicted schematically in Fig. 1A
. Briefly, 5 µg total RNA from TT1
cells were transcribed using random hexamers and AMV-RT (Promega
Corp., Madison, WI) and amplified using oligonucleotide primers
specific for mouse Pit-1 exons 1 (sense) and 3 (antisense), and an
aliquot of the reaction was electrophoresed on a 1.5% agarose gel and
stained with ethidium bromide. A portion of the first reaction was
subsequently reamplified with 200 ng of the identical exon 1 sense
primer and a 32P-labeled antisense oligonucleotide probe
(mixed with 150 ng unlabeled primer) common to mouse Pit-1ß/Pit-1T
(12). The probe was labeled to 1 x 109 cpm/µg with
T4 polynucleotide kinase (New England Biolabs, Inc.,
Beverly, MA) and [-32P]ATP (ICN Biochemicals,
Inc., Costa Mesa, CA). After the second round of PCR, products
were electrophoresed through a 5% polyacrylamide gel, and the gel was
dried and exposed to x-ray film for 4 h.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T1 cell line expresses and synthesizes Pit-1, as
determined by Northern and gel shift analysis (16). To refine the
analysis of Pit-1 populations in the TT1 cells, RT-PCR for Pit-1 and
two alternatively spliced isoforms, Pit-1ß and Pit-1T, that contain
an additional 78 or 42 nucleotides, respectively, was performed (Fig. 1
). Due to the lower abundance and similar size of the alternately
spliced isoforms compared with Pit-1, we used a nested PCR strategy to
distinguish them (Fig. 1A). Using an exon 1 sense strand primer with an
exon 3 antisense primer, we detected the major Pit-1 transcript in
TT1 cells by ethidium bromide staining after 25 cycles (Fig. 1B).
This PCR product comigrated with Pit-1 found in rat GH3
cells. Parallel PCR reactions with plasmids encoding full-length Pit-1,
Pit-1ß, and Pit-1T allowed us to distinguish the isoforms by size
(Fig. 1B). An aliquot of the reaction was subjected to a second round
of PCR using a 32P-labeled antisense primer specific for
Pit-1ß/Pit-1T with the same exon 1 sense primer, and the products
were electrophoresed on a 5% acrylamide gel followed by
autoradiography. Both Pit-1T and Pit-1ß were detected in TT1
cells, although the abundance of the former predominated (Fig. 1C). As
seen previously, only Pit-1ß was found in the rat GH3
cells, and as expected, no product was observed with the Pit-1 plasmid
control that lacks sequences present in the antisense primer. Again,
plasmid controls for Pit-1T and Pit-1ß allowed us to distinguish
between them. The existence of Pit-1 and its alternately spliced
isoforms in the TT1 cells defines them as differentiated thyrotropes
immortalized subsequent to the onset of Pit-1 expression.
Pit-1 expression alone does not define the cellular origin of the
TT1 cells, as the Pit-1 dependency of the pars tuberalis and pars
distalis thyrotropes in rodents remains controversial. It is known,
however, that the pars tuberalis thyrotropes of the rat are insensitive
to thyroidectomy and are not responsive to thyroid hormone (4, 7).
Therefore, to determine whether the TT1 cells were derived from the
pars tuberalis or the pars distalis, TT1 cells were analyzed for
their sensitivity to thyroid hormone inhibition. Initial studies were
undertaken to determine whether the TT1 cells express TRs. Like
Pit-1, the TR has multiple isoforms (TR1, TR2, TRß1, and
TRß2) (30, 31). As the TRß2 isoform is specific for the anterior
pituitary (30), Northern blot analysis and RT-PCR were performed to
determine whether the TT1 cells express either of the ß-isoforms
of the TR. A Northern blot using 8 µg poly(A)+ RNA and a
295-bp probe specific for the amino-terminus of mouse TRß1
demonstrated a single transcript of about 6.4 kb, consistent with its
previously determined size (Fig. 2) (10).
As the TRß2 isoform is less abundant, we used a PCR strategy to
detect a 512-bp product specific for the amino-terminus of this
receptor from TT1 cells (Fig. 2). An additional Northern blot
analysis demonstrated the presence of a 2.5-kb transcript for the
RXR isoform, which is a heterodimerization partner for thyroid
receptors and within the pituitary is restricted to thyrotrope cells
(32). Previous studies have demonstrated that RXR1 plays a unique
role in mediating ligand-dependent suppression by retinoids on TSHß
promoter activity (24).
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T1 cells were treated
with T3 and analyzed for effects on TSH subunit gene
expression. Before T3 treatment, TT1 cells were
maintained in medium containing 10% thyroid hormone-depleted serum for
2 days to ensure a hypothyroid condition. Subsequently, the cells were
treated with varying doses of T3 for 48 h. Northern
analysis of steady state levels of - and TSH ß-subunit mRNAs
showed a dichotomy between subunit gene regulation by thyroid hormone
(Fig. 3). Although the TSH ß-subunit
mRNA levels decreased with increasing concentrations of T3,
-subunit mRNA expression was unchanged (Fig. 3B). This finding is in
contrast with previous studies in which the expression levels of both
TSH subunit genes are inhibited by T3 treatment (33).
Quantification of pooled data from three independent experiments
indicated that the half-maximal inhibitory effect of T3 on
TSH ß-subunit mRNA levels occurred at 0.3 nM, similar to
previous observations of T3 inhibition of TSH synthesis
(34).
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PhosphorImager analysis of Northern blots from three independent
experiments demonstrated that although the -subunit mRNA remained
unchanged over the entire 72-h period, the inhibitory effect of
T3 on TSHß mRNA was apparent at 4–8 h. After 72 h,
TSH ß-subunit mRNA expression was near the limits of detection, and
thus further time points were not considered to represent accurate
determinations.
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T1 cells, the effect
of T3 treatment on the TSH ß-subunit mRNA decay rate was
examined after inhibition of new mRNA synthesis with DRB, an analog of
adenosine that selectively and reversibly blocks the synthesis of RNA
polymerase II transcripts without compromising cell viability (36). DRB
was chosen instead of the more commonly used actinomycin D, because
under our experimental conditions actinomycin D caused a paradoxical
increase, rather than a decrease, in control RNA levels (data not
shown). TT1 cells were initially treated with 100 nM
T3, and 24 h later, the cultures were exposed to DRB.
In so doing, regulation by T3 is permitted to proceed
before inhibition of de novo RNA synthesis. This is evident
in Fig. 5, which shows that TSH
ß-subunit expression in T3-treated cells is suppressed by
approximately 50% relative to that in untreated controls at the time
when DRB was added to the cultures (time zero). The TSH ß-subunit RNA
half-life was estimated by linear regression analysis of the decay in
mRNA levels with time, subsequent to DRB treatment. Because GAPDH mRNA
is not regulated by T3 in TT1 cells and showed no
decline during the 10-h exposure to DRB, it was used as an internal
control for loading. The apparent half-life of TSH ß-subunit
transcripts in TT1 cells was approximately 10 h in either the
presence or absence of T3. DRB had no effect on -subunit
mRNA levels, in agreement with previous reports, indicating that it is
an inherently stable RNA (23, 37). These data indicate that
T3 inhibition of TSH ß-subunit steady state mRNA levels
in TT1 cells is not attributable to a thyroid hormone-mediated
increase in the degradation rate of TSH ß-subunit mRNA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T1 thyrotrope line was derived from pituitary tumors of
transgenic mice bearing an oncogene controlled by 5.5 kb of the human
glycoprotein -subunit regulatory region (16). The development of a
thyrotrope cell line that is maintained continuously in culture created
a valuable tool for studies of thyrotrope biology. By maintaining these
cells under standard cell culture conditions, investigators have the
ability to ask mechanistic questions that, in some cases, are
unapproachable in primary cell cultures. Previous investigations of the
mechanisms that regulate TSH gene expression have used either primary
pituitary cells or the thyrotropic tumor cells, TtT-97. Because of the
inherent heterogeneity of the dispersed pituitary model, the difficulty
and expense in maintaining thyrotropic tumors in hypothyroid mice, and
their inability to survive culture conditions for extended periods of
time, their usefulness is limited. We have taken advantage of the
coexpression of the glycoprotein hormone -subunit and the TSH
ß-subunit gene in TT1 cells to evaluate their usefulness in future
studies as representative thyrotrope cells.
The thyrotrope population in the anterior pituitary is dynamic. In the
early stages of anterior pituitary differentiation, on approximately
embryonic day 14 (e14) in the rat, a subpopulation of cells that
express both -subunit and TSH ß-subunit resides in the rostral tip
of the anlagen of the anterior pituitary (3, 26). The expression of TSH
ß-subunit in these cells precedes the onset of expression of Pit-1
(26). This pattern of gene expression combined with the absence of
thyrotrope cells in the Snell dwarf mouse, which lacks functional
Pit-1, led to the hypothesis that the rostral tip or Pit-1-independent
thyrotropes are a transient population that does not persist in the
adult (38). However, at least two populations of thyrotropes are found
in the adult rodent pituitary: one population in the pars tuberalis and
a second in the pars distalis (5, 6). Although the Pit-1 dependence of
the pars tuberalis population is not definitively established in
rodents, the pars tuberalis and pars distalis thyrotropes can be
distinguished by their sensitivities to thyroid hormone (7). Based on
this defining characteristic, TT1 cells represent differentiated
thyrotrope cells of the pars distalis. Our findings demonstrate that
the TT1 cells express functional thyroid hormone receptors and that
physiological doses of T3 down-regulate TSH ß-subunit
gene expression in a manner that approximates in vivo
regulation.
The - and ß-subunits of TSH are differentially regulated by
T3 in TT1 cells. This is in contrast to what is reported
by in vivo (33, 39, 40, 41) and in vitro studies (8, 9, 42, 43, 44, 45). The lack of -subunit repression by T3 in
pure thyrotrope cell cultures may indicate that T3
regulation of the -subunit in heterogeneous systems is indirect. The
-subunit is differentially regulated in gonadotropes and thyrotropes
(46). The concurrent regulation of the same gene in multiple cell types
emphasizes the complexity of -subunit gene expression.
Alternatively, the lack of T3 repression of the -subunit
gene may be a consequence of the absence of T3 receptors or
a necessary corepressor in a subpopulation of cells in culture. Because
TT1 cells express high levels of -subunit RNA, and it is a very
stable mRNA, small changes in -subunit steady state mRNA levels may
not be detectable if not all the cells are responsive. A third
possibility is that the immortalization of these cells by simian virus
SV 40 T-antigen deregulation -subunit expression. Further analysis
of TR expression at the single cell level and direct gene transfer
studies using -subunit promoter constructs may resolve this
paradox.
TRs are nuclear transcription factors that regulate gene expression by
binding directly to DNA response elements. There are four isoforms of
the TR (1, 2, ß1, and ß2), three of which mediate thyroid
hormone function (1, ß1, and ß2) (30). These receptors are
present in early stages of embryonic development and, based on binding
studies, are functional on e13. The TR isoforms are present throughout
the developing nervous system, but the ß2 isoform is expressed only
in the anterior pituitary (30). By in situ hybridization,
TRß2 is detectable on e13.5 in the anterior pituitary anlagen, and
high levels of expression are exhibited by e19.5 (31). The TT1 cells
are fully differentiated based on the expression of Pit-1 and the
ß-subunit of TSH. Because TRß1 and TRß2 are present early in
anterior pituitary differentiation before TSH ß-subunit expression,
their expression in the TT1 cells is predictable if the TT1 cells
were derived from the pars distalis. Importantly, the TR identified in
TT1 cells are functional. The T3 sensitivity of the
TT1 cells presents the opportunity to investigate the mechanism by
which TR mediates repression of TSHß mRNA in thyrotropes.
Thyroid hormone does not affect the stability of TSH ß-subunit RNA in
TT1 cells. This finding in TT1 cells is in conflict with the work
performed in the rat pituitary by Krane et al. (35), which
showed that the decrease in TSH ß-subunit RNA stability in response
to T3 treatment is a consequence of poly(A) tail
shortening. In addition, the work of Leedman et al. (47)
demonstrated that T3 induced a specific RNA-binding protein
that may target the TSH ß-subunit RNA for deadenylation and
degradation. Our analysis of the degradation rate of TSH ß-subunit
mRNA was performed after a 24-h preincubation with T3
instead of blocking de novo RNA synthesis before
T3 treatment. The exposure of the cells to T3
before the inhibition of further RNA synthesis allowed us to examine
posttranscriptional effects independent of potential transcriptional
events that occur within the first 24 h after hormone treatment.
In addition, we did not observe any changes in the size of TSH
ß-subunit RNA upon T3 treatment even when Northern gels
were run in conditions that maximize resolution. The lack of
posttranscriptional regulation in the TT1 cells may therefore make
the TT1 thyrotropes a simplified model system for the future
analysis of T3 regulation directly at the transcriptional
level.
Pit-1 interacts with a number of classes of transcription factors on
various pituitary hormone genes to activate transcription (48, 49, 50).
Like the TR, Pit-1 has several isoforms. These include two insertion
variants that are localized to the activation domain: a 26-amino acid
insertion, Pit-1ß, and a 14-amino acid insertion that in mice is
restricted to thyrotropes, Pit-1T (12, 27, 28, 29, 51). Pit-1 and Pit-1T
synergistically activate the TSH ß-subunit in a promoter-specific
manner in transient transfection assays when coexpressed in TSH
thyrotrope cells and GH3 somatolactotrope cells (14).
However, these studies also implicate the requirement of cell
type-specific factors to maximize expression. The expression of Pit-1
isoforms in the TT1 cells provides a unique opportunity to study not
only thyrotrope-specific regulation of Pit-1, but also isoform-specific
regulation of gene transcription in cells that endogenously express TSH
ß-subunit. Further analysis of the mouse TSH ß-subunit promoter in
TT1 cells will identify T3-responsive regions and
address the possibility of coregulation of the TSH ß-subunit gene by
T3 and Pit-1.
In this study, we characterized the TT1 cell line as thyrotrope
cells that are derived from the pars distalis. They are responsive to
classical endocrine feedback by thyroid hormone and express isoforms of
TR and Pit-1 that are pituitary and thyrotrope specific, respectively.
Previous studies conducted in TtT97 cells have identified several
cis-acting elements that control both thyrotrope-specific
and thyroid hormone-regulated expression of the mouse TSH ß-subunit
gene. However, the heterogeneity of TtT97 cells has hindered progress
toward isolating the protein factors that bind these elements. The
clonal TT1 cells are an attractive alternative model system that
will facilitate the identification of both cis- and
trans-acting factors controlling thyrotrope-specific and
hormonally regulated expression of TSH subunit genes. The availability
of multiple thyrotrope model systems present the opportunity to
decipher thyrotrope- vs. model system-specific TSH gene
regulation.
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Acknowledgments |
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cDNAs, respectively. |
Footnotes |
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2 These authors contributed equally to the work.
3 Present address: Banting and Best Diabetes Center, The Toronto
Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
4 Present address: Department of Physiology, University of Wisconsin,
Madison, Wisconsin 53706.
Received March 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit gene promoter. Endocrinology 127:1352–1361[Abstract]
and ß thyroid hormone receptors from thyrotrope cells: the mouse
pituitary-specific ß2 isoform differs at the amino terminus from the
corresponding species from rat pituitary tumor cells. Mol Endocrinol 5:1049–1061[Abstract]
-subunit gene.
Mol Endocrinol 8:528–536[Abstract]
-subunit of mouse thyrotropin. Proc Natl Acad Sci USA 78:5329–5333T3–1 pituitary gonadotrope cells. Endocrinology 136:1361–1366[Abstract]
1 mediates 9-cis-retinoic acid
suppression of thyrotropin-ß promoter activity. Mol Endocrinol 11:481–489- and ß-thyroid hormone receptor mRNAs,
including the ß2-subtype, in the developing nervous system. J
Neurosci 12:2288–2302[Abstract]
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-gene in primary cultures of rat pituitary cells. Mol Endocrinol 7:797–805- and thryotropin (TSH) ß-subunit
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