Thyroid Hormone-Responsive Pituitary Hyperplasia Independent of Somatostatin Receptor 2
Michelle L. Brinkmeier,
Justin H. Stahl,
David F. Gordon,
Brian D. Ross,
Virginia D. Sarapura,
Janet M. Dowding,
Susan K. Kendall,
Ricardo V. Lloyd,
E. Chester Ridgway and
Sally A. Camper
Department of Human Genetics (M.L.B., J.H.S., S.K.K., S.A.C.),
Departments of Radiology and Biological Chemistry (B.D.R.), University
of Michigan, Ann Arbor, Michigan 48109; Division of Endocrinology,
Metabolism, and Diabetes (D.G., V.D.S., J.M.D., E.C.R.), University of
Colorado Health Sciences Center, Denver, Colorado 80262; and Division
of Anatomic Pathology (R.V.L.), Mayo Clinic, Rochester, Minnesota
55905
Address all correspondence and requests for reprints to: Dr. Sally Camper, Department of Human Genetics, University of Michigan Medical School, 1500 West Medical Center Drive, 4301 MSRB III, Ann Arbor, Michigan 48109-0638.
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ABSTRACT
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Mice homozygous for the targeted disruption of the
glycoprotein hormone
-subunit (
Gsu) display
hypertrophy and hyperplasia of the anterior pituitary thyrotropes.
Thyrotrope hyperplasia results in tumors in aged
Gsu-/- mice. These adenomatous
pituitaries can grow independently as intrascapular transplants in
hypothyroid mice, suggesting that they have progressed beyond simple
hyperplasia. We used magnetic resonance imaging to follow the growth
and regression of thyrotrope adenomatous hyperplasia in response to
thyroid hormone treatment and discovered that the tumors retain
thyroid hormone responsiveness. Somatostatin (SMST) and its diverse
receptors have been implicated in cell proliferation and tumorigenesis.
To test the involvement of SMST receptor 2 (SMSTR2) in pituitary tumor
progression and thyroid hormone responsiveness in
Gsu-/- mutants, we generated
Smstr2-/-,
Gsu-/- mice.
Smstr2-/-,
Gsu-/-
mice develop hyperplasia of thyrotropes, similar to
Gsu-/- mutants, demonstrating that
SMSTR2 is dispensable for the development of pituitary adenomatous
hyperplasia. Thyrotrope hyperplasia in
Smstr2-/-,
Gsu-/- mice regresses in response to
T4 treatment, suggesting that SMSTR2 is not required in the
T4 feedback loop regulating TSH secretion.
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INTRODUCTION
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MANY LINES OF evidence support a role for
somatostatin (SMST) and its receptors in regulation of TSH
secretion in normal and hypothyroid animals (1, 2). SMST
is a hypothalamic peptide that has roles in inhibiting a variety of
physiological activities in many organs including the inhibition of GH,
PRL, and TSH secretion, and the inhibition of cell proliferation
(3). SMST effects are controlled through five receptors,
SMSTR15, all of which are expressed in the anterior pituitary gland
(4, 5, 6, 7).1
Thyrotropes express predominantly Smstr1, Smstr2, and
Smstr5, but little or no Smstr3 and
Smstr4 (10, 11). Regulation of TSH secretion by
somatostatin appears to be mediated by both SMSTR2 and SMSTR5
(12). Thus, thyrotrope responsiveness to SMST probably
involves Smstr1, Smstr2, and/or
Smstr5.
Studies on large numbers of human tumor types, including pituitary
adenomas, have shown that most tumors express high levels of at least
one SMSTR subtype. More than 80% of the time the subtype expressed is
Smstr2 (13, 14). GH- and TSH-producing
pituitary adenomas express increased levels of Smstr2
compared with the normal gland (15). The SMST analog,
octreotide, has been used to treat TSH-secreting tumors when options
such as surgery or radiotherapy are not feasible. Octreotide binds with
the highest affinity to SMSTR2 followed by SMSTR5 and SMSTR3
(15). This is consistent with the idea that
Smstr2 is important in thyrotrope adenomas.
Thyrotropic tumor cells, TtT97, grown in hypothyroid mice,
have been used as a model to study hormone responsiveness of
thyrotropes (1). TtT97 tumors propagated in
hypothyroid mice shrink in response to T4. The
expression of Smstr2 is maintained while Smstr1
and Smstr5 increased in response to T4
(1). Rats rendered hypothyroid with antithyroid drugs
exhibit alterations in Smstr1 and Smstr2 RNA
levels in response to T3 treatment
(2). These studies implicate a role for Smstr1,
Smstr2, and Smstr5 in the negative feedback loop
regulating TSHß transcription in response to thyroid hormone.
We have used
Gsu-/- mice as a model for
hypothyroidism with increased TSHß transcription (16).
The diffuse thyrotrope hyperplasia seen in
Gsu-/- mice is different in appearance from
the focal hyperplasia induced in normal adult mice rendered hypothyroid
by chemical or radiation treatment. This suggests that early onset
hypothyroidism has the potential to recruit more pituitary precursors
to the thyrotrope fate. We demonstrate progression of global thyrotrope
hyperplasia in
Gsu-/- mice into
transplantable adenomatous hyperplasia that retains
T4 responsiveness. Using Smstr2 and
Gsu double knockout mice, we have shown that despite
previous studies suggesting its involvement, SMSTR2 is not required for
tumor progression or thyroid hormone responsiveness in this thyrotrope
tumor model.
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RESULTS
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Progression of Thyrotrope Hyperplasia in Aging
GSU-/- Mice
At 2 months of age
Gsu-/- mice
exhibited thyrotrope hypertrophy and hyperplasia with little or no
significant change in pituitary size (17). We aged
Gsu-/- mice to assess whether the
thyrotrope hyperplasia would progress. At approximately 1 yr of age,
all mice had pituitary masses that were larger than the average
wild-type pituitary, although the size of the pituitary masses varied
considerably (Fig. 1
).

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Figure 1. Progression of Thyrotrope Hyperplasia to
Transplantable Tumors
Pituitary glands from approximately 1-yr-old wild-type (A) and
Gsu-/- mice (B and C) demonstrate an
increase in pituitary size in the
Gsu-/- mice from 5-fold (B) to
47.1-fold (C) compared with wild-type (A). Black
bar = 3 mm. D, Pituitary masses continue to grow when
transplanted between the scapula of hypothyroid C57BL/6 mice.
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The pituitaries of the mutant mice could be classified in two groups.
One group had pituitaries that retained a lobular structure (Fig. 1B
).
These pituitaries exhibited a 5- to 10-fold increase in weight (Table 1
). The other group had completely lost
the lobular pituitary structure and had markedly increased
vascularization and necrotic areas in the portion of the gland that had
undergone the most dramatic growth (Fig. 1C
). This group had pituitary
weights that were approximately 30- to 50-fold above normal (Table 1
).
These large masses exhibited increased mitotic activity and absence of
other cell types within the proliferating population, consistent with
progression to adenomas (data not shown).
Pituitaries from four 12-month-old
Gsu-/- mice were removed and transplanted
into C57BL6/J male mice rendered hypothyroid 6 wk before transplant via
radiothyroidectomy. After 6 months, hyperplastic pituitaries
ranging initially from 34 mg to 88 mg increased in weight to 35 g
(Fig. 1
D), which represents a 50- to 100-fold increase in weight. This
suggests that growth of the adenomatous hyperplastic masses is
independent of the normal pituitary surroundings.
Thyroid Hormone Treatment of
Gsu-/-
Mice Results in Regression of Hyperplasia
Thyroid hormone (T4) treatment can prevent
and reverse hypertrophy and hyperplasia of thyrotropes in
Gsu-/- neonates and young adults,
respectively (17).
Gsu-/- mice
ranging from 711 months of age were treated with
T4 injections for 40 d to test whether the
pituitary hyperplasia would respond in a similar manner to the hormone
regimen as the younger
Gsu-/- mice and the
TtT97 tumors (1). Because of the variation in size of
pituitary masses, the pituitary volumes of eight
Gsu-/- mice were measured by magnetic
resonance imaging (MRI) and placed into two groups, control and
T4 treated (Fig. 2
). This strategy made it possible to
monitor growth and regression longitudinally by carrying out repeat MRI
studies after 21 and 40 days (Fig. 2
). Longitudinal monitoring of
individual mice via MRI provides an accurate assessment of mass growth
and regression during the treatment regimen and is an attractive
alternative to killing groups of mice at each time point.

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Figure 2. MRI Permits Noninvasive Examination of Pituitary
Volume
T2-weighted magnetic resonance images were used to document
the size of pituitary glands in 9-month-old
Gsu-/- mice at 0, 21, and 40 d of
thyroid hormone treatment (panels AC) compared with aged matched
wild-type littermates (panel D). Midsagittal image reveals the
olfactory lobe (OL), cerebellum (CE), spinal cord (SC), and pituitary
gland (between arrowheads). Each displayed image is from
approximately the same region of the brain.
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At the beginning of the experiment, the 7- to 10-month-old wild-type
mice had an average pituitary volume of 3 mm3
(Table 2
). The pituitary volumes of 7- to
9-month-old
Gsu-/- mice were larger,
ranging from 5 to 8 mm3. The starting pituitary
volumes of 11-month-old
Gsu-/- mice were
substantially larger than normal, ranging from 8 to 18
mm3. Note that the midsagittal pituitary diameter
is as large as the cerebellum at its widest point.
Changes in pituitary volumes were observed at d 21 and d 40 in both
groups (Fig. 3
). All individuals in the
T4-treated group had significant reduction in the
size of the pituitary mass at both time points. Volumes decreased in
T4-treated
Gsu-/-
mice from 37 to 71% of the starting volume. Over the same time
interval the untreated
Gsu-/- mice
exhibited 21117% increases in volume (Table 2
). This demonstrates
that the thyroid hormone treatment rapidly arrested growth and induced
remarkable regression of the adenomatous hyperplasia.
SMSTR2 Is Not Required for the Progression of Hyperplasia in
Gsu-/- Mice
SMSTRs have been shown to be expressed at high levels in
many human tumor systems (15, 18, 19). In addition,
Smstr2 is expressed at high levels in some neuroendocrine
tumors (20) as well as pituitary somatotrope adenomas
(21). Smstr2 transcripts were detected by
Northern analysis in transplanted
Gsu-/-
pituitary masses (Fig. 4
); however,
Smstr3 and Smstr4 were not detected (data not
shown). We used mice with targeted disruptions in Smstr2
(22) to test whether Smstr2 is involved in the
thyrotrope hyperplasia or T4-induced regression
observed in
Gsu-/- mice. Mice were bred to
produce double mutants with targeted disruptions to both
Smstr2 and
Gsu. If SMSTR2 is necessary for the
development of the thyrotrope adenomatous hyperplasia in
Gsu-/- mice, disrupting Smstr2
in the
Gsu-/- mice should prevent it.
Double heterozygous matings are expected to produce
Smstr2-/-,
Gsu-/-
mice at a frequency of 1/16 (6.25%). We observed 3.2%, which is
slightly less than what is expected, P = 0.03.

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Figure 4. Northern Blot Analysis of Smstr2
Transcripts in polyA(+) RNA Derived from an
Gsu-/- Mouse Pituitary Gland
Transplanted into a Hypothyroid C57BL/6 Mouse
DNA size standards are shown on the left. The
autoradiograph was exposed for 5 d at -80 C.
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Six Smstr2-/-,
Gsu-/- mice were generated and killed at
26 months. Thyrotrope hypertrophy and hyperplasia were analyzed
by immunohistochemistry with antibodies to TSHß (Fig. 5
). The double knockouts were compared
with single mutants and double heterozygote littermate controls. In
Smstr2-/-,
Gsu-/- pituitaries the immunoreactive
TSHß cells were enlarged and present throughout the pituitary in
great abundance. This extensive hypertrophy and hyperplasia of
thyrotropes in Smstr2-/-,
Gsu-/- mice are indistinguishable from
those observed in
Gsu-/- mice (Fig. 4
).
These results indicate that thyrotrope hyperplasia can develop in
Gsu-/- mice in the absence of
Smstr2.

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Figure 5. Thyrotrope Hypertrophy in T4-Treated
and Untreated Smstr2-/-,
Gsu-/- Pituitaries Demonstrated by
Immunohistochemistry with Antibodies to TSHß
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Thyrotrope Hyperplasia Decreases in
Smstr2-/-,
Gsu-/-
Mice Treated with Thyroid Hormone
Thyrotrope hyperplasia decreases in
Gsu-/- mice in response to
T4 treatment (17). Increased levels
of T4 stimulate SMST secretion, which negatively
regulates TSHß secretion. To determine whether
Gsu-/- mutants respond appropriately to
T4 in the absence of SMSTR2,
Smstr2-/-,
Gsu-/-
mice were treated for 40 d with T4.
Immunohistochemistry with TSHß antibodies was used to assess
thyrotrope hyperplasia (Fig. 5
). Pituitaries from
Smstr2-/-,
Gsu-/-
mutants responded to T4 treatment in a similar
manner as
Gsu-/- single mutants, as
indicated by a reduction in the number and size of TSH-staining
thyrotropes to wild-type levels. These results indicate that SMSTR2 is
not required for T4-mediated TSHß
down-regulation.
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DISCUSSION
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Thyrotrope hyperplasia progresses to adenomatous hyperplasia in
1-yr-old
Gsu-/- mice. Pituitary masses from
1-yr-old
Gsu-/- mice display tumor
characteristics such as increased vascularization, increased mitotic
activity, and regions of proliferating thyrotropes (Fig. 5
) devoid of
other pituitary cell types. Transplantation of these pituitary adenomas
into hypothyroid C57BL/6 mice has demonstrated the ability of these
masses to grow independently of endogenous factors specific to the
pituitary gland and immediately surrounding milieu. There was no
evidence of metastasis or invasiveness.
SMSTRs have been detected at high levels in many tumor types including
pituitary adenomas (12, 18).
Smstr2-/-,
Gsu-/-
mice exhibited thyrotrope hyperplasia by 3 months of age. Thyrotrope
hyperplasia is reversed in Smstr2-/-,
Gsu-/- mice treated with
T4. These results suggest that SMSTR2 is not
required for thyrotrope hyperplasia or thyroid hormone responsiveness
in
Gsu-/- mice. SMST may bind to a receptor
other than SMSTR2 in the down-regulation of TSHß or one of the other
receptors present in thyrotropes may compensate for the absence of
SMSTR2 in Smstr2-/-,
Gsu-/- mice.
In humans, autopsy studies reveal that the development of pituitary
adenomas is a relatively common event, with a frequency of
approximately 20% in the general population (23).
Although TSH-secreting tumors represent only 12% of pituitary
adenomas, they are generally large macroadenomas at the time of
diagnosis (24, 25, 26). Patients symptoms vary according to
the hormones produced by the adenoma and can include severe
hyperthyroidism, goiter, clinical acromegaly, galactorrhea, amenorrhea,
visual field defects, and headaches. Treatment for adenomas also
varies. TSH-secreting tumors are generally removed by transsphenoidal
surgery and, when this is not sufficient for remission, radiation
and/or adjuvant medical therapy follows. The SMST analog octreotide has
been shown to be effective for many patients in reducing the size of
the tumor as well as suppressing TSH levels. In contrast to the
Gsu-/- mice, administration of
T4 is usually not beneficial for treatment of
TSH-producing adenomas in humans because high levels of thyroid hormone
are usually already present secondary to the elevated TSH levels
(25). However, T4 treatment can
reduce the size of tumor-like nodules with TSH cell hyperplasia in
humans (27).
At this time, the etiology of pituitary adenomas is not well understood
(23, 28). Studies have been performed to identify and
analyze genes that play a role in the initiation and progression of
these tumors. LOH at several chromosomal loci (on 10q, 11q, 13q, and
9p) has been identified in some patients, but the critical genes in
these regions have not been identified (29). However,
several other critical genes have been identified (30).
The gene for the G protein involved in GHRF receptor signaling
(G
s or GNAS1) is altered in
many GH-secreting neoplasms (31), and MEN1
(multiple endocrine neoplasia type 1) mutations lead to
prolactinomas (32, 33, 34). Also, the pituitary tumor
transforming gene (PTTG) is associated with a variety of
tumor types (35). In mice, pituitary tumors within the
intermediate and anterior lobes result from deletion of the specific
CdK inhibitor genes encoding p27KIP1 (36) and p18INK4c
(37) that are expressed in the normal murine pituitary.
Although there has been significant progress in the molecular genetics
of pituitary adenomas, the generation of animal models will be
important to further understand the etiology of these tumors. In
addition, these models, including the
Gsu-/- mouse, may facilitate the
development of improved treatment strategies for anterior pituitary
adenomas.
Many cell lines exist that are representative of the five cell types
present in the anterior pituitary gland. Currently, the
TSH
(38) cell line, the TtT97 tumors (39), and
T
T1 cell lines (40) are available as readily
manipulable models of normal thyrotrope cells. The TtT97 cells were
derived from hyperplastic pituitaries in hypothyroid LAF1 mice, express
TSHß, and are T4 responsive. They are
cumbersome, expensive, and time consuming to maintain because they must
be generated from tumors that are propagated by transplantation. The
TSH cell line represents a primordial thyrotrope that does not
express TSHß. While the T
T1 cell line does express TSHß and is
T4 responsive, the cells express SV40 large
T-antigen and are somewhat difficult to grow and transfect. As a
complement to T
T1, a stable cell line that expresses TSHß and is
T4 responsive would be a valuable tool for
studying transcriptional control and thyroid hormone responsiveness. We
have shown that thyrotrope hyperplasia in the pituitary glands of
Gsu-/- mice can result in transplantable
pituitary masses of several grams. We have also demonstrated that these
tumors are T4 responsive. Therefore, these mice
could be used as a rich source of rapidly growing thyrotropes to
generate a stable T4 responsive thyrotrope cell
line. Such a cell line would be useful for studies involving fully
differentiated, thyroid hormone-responsive, thyrotropes.
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MATERIALS AND METHODS
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Propagation and Genotyping Mice
Targeted disruption of
Gsu was accomplished by
gene targeting, and the mice (Cgatm1,
or
Gsu-) were deposited at The Jackson Laboratory (Bar Harbor, ME) (16). A colony of
Gsu+/- with mixed genetic background
(129 and C57BL/6J) mice have been maintained at The University of
Michigan. Due to the hypothyroid state of the
Gsu-/- mice, they remain with their parents
or are housed with normal littermates to maintain the appropriate body
temperature. Mice were genotyped with genomic DNA prepared from tail
biopsies by PCR analysis (16).
Smstr2-/- mice were obtained from Merck
Research Laboratories (Rahway, NJ).
Smstr2-/- were mated with
Gsu+/- mice and
F1 Smstr2+/-,
Gsu+/- mice were intercrossed to generate
mice heterozygous and homozygous for both Smstr2 and
Gsu.
Gsu alleles were genotyped as
previously described (16). Smstr2 alleles were
identified with two sets of primers amplified at 95 C for 5 min, 35
cycles of 94 C for 30 sec, 61 C for 2 min, 72 C for 2 min, followed by
72 C for 10 min. Primers used to identify the wild-type allele,
for(5'-AGG TGA GGA CCA CCA CAA AG-3') and rev(5'-ATC CGG GGC TTG GTA
CAC AG-3') amplified a 306-bp product. Primers used to identify the
disrupted allele, for(5'-TGA CAA ATG GAA GTA GCA CGT CTC ACT AGT CT-3')
and rev(5'-GAT CTC TAG GCA GCT TGG TTC T-3') amplified a 281-bp
product. Thyroid hormone injections were performed for 40 d as
previously described (17). All procedures using mice were
approved by the University of Michigan and the University of Colorado
Health Sciences Center Committee on Use and Care of Animals. All
experiments were conducted in accord with the principles and procedures
outlined in the NIH Guidelines for the Care and Use of Experimental
Animals.
Adenomatous Hyperplasia Growth in Hypothyroid Mice
Pituitary masses from 1-yr-old
Gsu-/- mice were removed, weighed, minced
in 0.9% sterile NaCl, and transplanted sc between the scapulas of
hypothyroid C57BL/6 male mice. After monitoring growth of the pituitary
tumor for 6 months, it was removed, weighed, and analyzed
further.
MRI
In vivo magnetic resonance imaging experiments were
performed on a Varian MRI system equipped with a 7 tesla, 18.3-cm
horizontal bore magnet (Oxford Instruments, Concord, MA) as previously
described (41). In brief, for MRI examination, mice were
anesthetized with sodium pentobarbital (6070 mg/kg, ip) and
positioned within a 3-cm diameter quadrature radio-frequency coil (USA
Instruments, Aurora, OH). A single-slice gradient-recalled echo
image was acquired with 1-mm saturation cross-hairs imprinted on the
axial and coronal images to facilitate rapid and reproducible
positioning on the animal. Multislice T2-weighted
sagittal images were acquired by using a spin echo sequence with the
following parameters: 2.5-sec repetition time, 60-ms echo time, field
of view = 25 x 25 mm using a 128 x 128 matrix, slice
thickness = 0.5 mm, slice separation = 0.8 mm, number of
slices = 15, and eight signal averages per phase encode step.
Pituitary volumes were obtained from the multislice magnetic resonance
images by electronically outlining the region of interest using image
processing software (Advanced Visual Systems, Waltham, MA) as
previously described (42). The number of pixels was
converted to an area on all slices, multiplied by the slice
separation.
Northern Analysis
RNA isolation, purification of polyA(+) RNA, and analysis of
steady-state mRNA levels were performed using methods that have been
previously described (1). The cDNA encoding mouse
Smstr2 was kindly provided by Dr. Graeme Bell (University of
Chicago, Chicago, IL). Five micrograms of poly(A)+ RNA were separated
by electrophoresis through a 0.8% agarose-6% formaldehyde gel,
transferred to a Nytran filter and hybridized to a radiolabeled mouse
Smstr2 cDNA probe. The autoradiograph was exposed for 5
d at -80 C with an intensifying screen.
Immunohistochemistry
Pituitary glands were removed, fixed overnight in 4%
buffered paraformaldehyde, embedded in paraffin, and sectioned at 4
µm. Immunohistochemistry was performed with polyclonal antisera
against rat TSHß (1:1000, no. AFP1274789, National Hormone and
Pituitary Program, National Institute of Diabetes and Digestive and
Kidney Diseases, Bethesda, MD). Biotinylated secondary
antibodies were used in conjunction with avidin and biotinylated
peroxidase (Vectastain rabbit kit, Vector Laboratories, Inc., Burlingame, CA) with diaminobenzidine as the
chromogen. Normal serum was substituted for the primary antibody in
negative controls. Sections were counterstained with Gills triple
strength hematoxylin (Fisher Scientific, Pittsburgh,
PA).
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ACKNOWLEDGMENTS
|
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We would like to thank Dr. R. Andrew James, Department of
Medicine, University of Newcastle (Newcastle-upon-Tyne, UK), and
Novartis Pharma AG (Newcastle-upon-Tyne, UK), for their contributions
during the early stages of this work; Dr. Hilary A. Wilkinson from
Merck Research Laboratories (Rahway, NJ) for the
Smstr2-/- mice; Tennore Ramesh, Amy Radak,
Autumn Wenglikowski, and Mary Anne Potok for their help with the
maintenance and genotyping of the mice; and the University of Michigan
Morphology Core (Ann Arbor, MI), especially Kay Brabec, for the use of
their equipment and helpful discussions.
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FOOTNOTES
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This work was supported by NIH Grants HD-34283 (to S.A.C.),
HD-30428 (to S.A.C.), R24-CA83099 (to B.D.R.), CA-47411 (to
E.C.R.), and DK-36843 (to E.C.R.).
Abbreviations:
GSU, glycoprotein hormone
-subunit; MRI,
magnetic resonance imaging; SMST, somatostatin; SMSTR, SMST
receptor.
Received for publication April 26, 2001.
Accepted for publication August 27, 2001.
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