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Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536
Address all correspondence and requests for reprints to: James F. Hyde, Ph.D., Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, 800 Rose Street (MN224), Lexington, Kentucky 40536-0084. E-mail: jfhyde00{at}pop.uky.edu
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Introduction |
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Galanin is principally localized in lactotrophs in female rats (6, 10, 11), especially after estrogen treatment. We reported that estrogen stimulates a similar pattern of secretion of galanin and PRL in vitro (12), and that galanin and PRL peptides are located within the same secretory granules in lactotrophs of estrogen-treated rats (13). Moreover, we demonstrated that galanin stimulates PRL secretion in both autocrine and paracrine manners in estrogen-treated rats (14). During pituitary hyperplasia induced by estrogen, galanin expression was increased in concert with the proliferation of lactotrophs. Removing the estrogen implants not only abated the accelerated growth of the pituitary, but also diminished the expression of galanin (10). This suggests that galanin may mediate the process of pituitary hyperplasia. However, it is difficult to distinguish whether the stimulatory effect of galanin on the proliferation of lactotrophs is dependent on estrogen.
The low abundance of galanin in the anterior pituitary under normal physiological conditions makes it difficult to study its functions. By generating galanin transgenic mice that express much higher amounts of galanin in the anterior pituitary, especially lactotrophs, we are able to delineate whether galanin is functionally independent of the actions of estrogen. We sought to determine whether galanin itself is capable of regulating PRL secretion or if galanin requires estrogen to regulate PRL expression and to result in pituitary hyperplasia.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) was transfected into
GH3 rat pituitary cells, which synthesize and secrete
copious amounts of PRL, but do not express the endogenous galanin gene.
GH3 rat pituitary cells (500,000 cells/35-mm2
petri dish) were transiently transfected with the transgene using
lipofectin reagent (Life Technologies, Inc., Grand Island,
NY). Conditioned medium from both normal (mock transfected) and
transfected GH3 were collected 48 h later and tested
for the presence of galanin peptide by RIA. Immunoreactive galanin
peptide was readily detected in medium from GH3 cells
transiently transfected with the transgene (550 pg/ml), whereas no
galanin immunoreactivity was detected in medium from mock-transfected
GH3 cells (<5 pg/ml). Analysis of the culture medium from
the transfected GH3 cells by HPLC showed that the
immunoreactive galanin coeluted with synthetic galanin-(1–29). Thus,
we showed that the transgene was capable of producing high levels of
galanin peptide.
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Tissue collection and procedures
Characterization of overexpression of galanin in the anterior
pituitary. Male and female transgenic and control mice from all
three lines (n = 12–20 animals/genotype/gender/transgenic line)
were killed between 1000–1400 h. Animals were divided into four
experimental subgroups. In the first experimental group, anterior and
posterior pituitaries and hypothalami were collected and frozen on dry
ice. The tissues were homogenized in ice-cold 1.0 N acetic
acid, and galanin peptide contents were quantified by RIA as previously
described (16). In the second experimental subgroup, the anterior
pituitary gland, hypothalamus, liver, spleen, skeletal muscle, heart,
fat, testis, and ovary were collected and frozen in liquid nitrogen.
RNA was extracted to measure galanin gene expression by Northern blot
analysis (15). Whole pituitaries of the third experimental group were
collected and frozen on dry ice, and 12-µm sections were cut on a
cryostat. In situ hybridization was performed to localize
galanin gene expression in the pituitary gland (14). In the last
experimental group, the anterior pituitary was enzymatically dispersed,
and the cells (30,000 cells/well) were cultured in a 96-well culture
dish coated with poly-D-lysine (0.5 g/100 ml; Sigma Chemical Co., St. Louis, MO). After overnight incubation, the
pituitary cells were washed twice (15 min each time) with medium 199
containing 0.1% BSA and then incubated for varying periods of time
(0.5, 1, 2, or 3 h) to measure galanin peptide secretion.
Characterization of pituitary hormone expression in transgenic mice. Male and female transgenic and control mice (from lines 1402–2 and 1427–7, a low galanin-expressing line and a high galanin-expressing line), at 2–4 months of age (n = 8–10 animals/genotype/gender/transgenic line), were used for the following studies. Animals were divided into two subgroups. Animals were killed between 1000–1400 h. Trunk blood was collected to measure plasma levels of PRL and GH. Anterior pituitaries from one group of animals were frozen, and proteins were extracted with 1.0 N acetic acid to measure PRL, GH, TSH, and LH contents using RIA. No differences in pituitary hormone contents were detected between the transgenic lines. Therefore, we combined the data. As we did not detect dramatic differences among the three lines of transgenic mice, we combined animals from all lines for the following studies. Anterior pituitaries from a second group of mice were collected on dry ice, and total RNA was extracted. Steady state PRL and GH messenger RNA (mRNA) levels were measured using ribonuclease protection assays (17).
Characterization of pituitary hyperplasia and hyperprolactinemia in transgenic mice. Male and female transgenic and control mice at 2–4, 6–10, and 11–17 months of age (n = 4–10 animals/genotype, gender, and age) were used for the following studies. Trunk blood was collected to measure plasma PRL. Anterior pituitaries were dissected and enzymatically dispersed. Cell count was conducted using a hemacytometer (Fisher Scientific, Pittsburgh, PA). Cells were then placed on microscope slides and fixed in 4% paraformaldehyde to measure PRL gene expression at the level of the individual cell by in situ hybridization.
Estrogen regulation of pituitary hyperplasia and PRL secretion in
transgenic mice
Male and female normal and transgenic mice were used at 11–13
months of age (n = 6–10 animals/gender and genotype). Half of the
female normal and transgenic mice were bilaterally ovariectomized after
anesthesia with metofane (methoxyflurane; Pitman-Moore, Inc.,
Mundelein, IL). The remaining females with intact ovaries served as
controls. Half of the male normal and transgenic mice were implanted sc
with a 17ß-estradiol capsule as described previously (14), and the
remaining males served as controls. Six weeks later, all animals were
killed. The anterior pituitaries were weighed and then enzymatically
dispersed. Pituitary cells (30,000 cells/well) were cultured in a
96-well culture dish coated with poly-D-lysine (0.5 g/100
ml; Sigma Chemical Co.). After an overnight incubation,
the cells were washed twice (15 min each time) with medium 199
containing 0.1% BSA, and then a 15-min static incubation was performed
to measure PRL secretion.
RIAs
Galanin peptide (16) and pituitary protein hormone (PRL, GH,
TSH, and LH) contents as well as plasma levels of PRL and GH were
determined by RIA (18, 19). Tissue extraction for hormone content was
performed as previously described (16). Briefly, tissues were sonicated
in 0.5 ml ice-cold 1.0 N acetic acid. The homogenates were
placed in a boiling water bath for 10 min, then centrifuged for 10 min
at 10,000 x g. The supernatants were lyophilized and
stored at -20 C until assayed for hormone contents.
Ribonuclease protection assays
PRL and GH mRNAs in the anterior pituitary were measured using a
ribonuclease protection assay as previously described with
modifications (17). The complementary DNAs for PRL and GH were obtained
from Drs. J. D. Baxter and R. Maurer, respectively. The
complementary RNA (cRNA) probes for PRL and GH were transcribed
in vitro with 5.5% and 1.65% of
[
-32P]UTP, respectively. Glyceraldehyde-3-phosphate
dehydrogenase (GAPDH; Ambion, Inc., Austin, TX) was used
as an internal control. One microgram of total anterior pituitary RNA
was hybridized with the cRNA probes overnight at 45 C, followed by
ribonuclease A/T1 digestion. The protected bands were separated on a
6% denatured polyacrylamide gel. The protected bands were 430, 380,
and 134 bp for PRL, GH, and GAPDH, respectively. The gels were dried,
and the protected products were quantified using a PhosphorImager
(Molecular Dynamics, Inc., Sunnyvale, CA). Ratios for the
integrated densities from PRL, GH, and GAPDH were used for statistical
analysis.
In situ hybridization
The PRL complementary DNA described above was also used for
in situ hybridization (14). The cRNA probe was transcribed
in vitro with [-35S]UTP. The dispersed
anterior pituitary cells were fixed in 4% paraformaldehyde, then
sequentially washed in 0.1 M phosphate buffer,
diethylpyrocarbonate-treated water, acetic anhydride (0.25%) diluted
in 80 mM (pH 8.0) triethanolamine buffer, and 2 x SSC
(1 x SSC = 0.15 M NaCl and 0.015 M
sodium citrate). Hybridization buffer (25 µl; Amresco, Solon, OH)
containing 0.3 µg/ml PRL cRNA was applied to each slide. After
overnight hybridization at 55 C, the slides were treated with
ribonuclease A (20 mg/ml) to digest unhybridized PRL cRNA. After
sequential washes in 0.2 x SSC at room temperature, the slides
were stringently washed in 0.1 x SSC at 60 C for 1 h. The
slides were briefly dehydrated, then dipped in 1:1 diluted
Kodak NTB-2 emulsion (Eastman Kodak Co.,
Rochester, NY) and exposed for 1 week to visualize the hybridized
signals.
Statistical analysis
Three-way ANOVA was used to analyze the main effects of gender,
genotype, and age on plasma PRL levels and pituitary cell numbers.
Two-way ANOVA was used to analyze the effects of gender and
genotype on galanin peptide contents, galanin secretion, and
pituitary hormone contents and gene expression. Post-hoc
comparisons were performed using Newman-Keuls multiple range tests
where appropriate (20).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) in potential founder mice
was confirmed by slot blot and Southern blot hybridizations using
genomic DNA isolated from tail biopsies. Analysis of 35 mice identified
4 potential founders, 2 females () and 2 males
(), that contained high copy numbers of the galanin
transgene. Transgenic female mice were mated with normal male mice, and
transgenic male mice were mated with normal female mice. The transgene
was transmitted to offspring in lines 1427–7, 1402–2, and 1415–3.
One transgenic founder mouse () was infertile. All transgenic
mice used in this study were heterozygous for the transgene.
Overexpression of galanin in the anterior pituitary of 2- to
4-month-old transgenic mice
Figure 2 shows the dramatic increase
in galanin gene expression in the anterior pituitary glands of both
male and female transgenic mice in all three transgenic lines () as determined by Northern blot analysis. The size
of the galanin transcript was identical in transgenic and normal mice.
We also performed Northern blot analyses using RNA from other tissues,
including hypothalamus, heart, spleen, skeletal muscle, ovary, testis,
and fat. Galanin gene expression in these tissues was not altered in
transgenic mice (data not shown). In situ hybridization
showed that the increase in galanin gene expression in the pituitary
gland was restricted to the anterior lobe (Fig. 3). Galanin mRNA signals in the anterior
pituitary were undetectable in normal male mice, but were readily
detectable in transgenic male mice. Normal female mice had detectable
levels of galanin mRNA in the anterior lobe of the pituitary gland, and
a dramatic increase in galanin gene expression was detected in
transgenic female mice (Fig. 3). No hybridization signal was evident
using a sense galanin cRNA probe (data not shown).
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). There were 82-, 74-, and
15-fold increases in female and 73-, 58-, 27-fold increases in male
transgenic mice of the 1427–7, 1415–3, and 1402–2 lines,
respectively, compared with control mice. Galanin peptide contents in
the anterior pituitary gland of female transgenic were significantly
higher than those in male transgenic mice (P < 0.05).
There were no changes detected in immunoreactive galanin peptide
contents of posterior pituitary (neurointermediate lobe) or
hypothalamus (data not shown).
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Using pituitary cells obtained from normal male and female mice,
galanin peptide secretion into the culture medium was undetectable
(<10 pg/well). In contrast, galanin peptide secretion was readily
detectable from pituitary cells of both male and female transgenic mice
(Fig. 5B). Pituitary cells from transgenic female mice secreted
significantly greater amounts of galanin peptide than pituitary cells
obtained from transgenic males after 3 h in culture
(P < 0.05).
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). Two-way ANOVA revealed a main effect
of gender (P < 0.0001), genotype (P <
0.005), and an interaction of gender and genotype (P <
0.05) in PRL contents. Multiple comparisons testing indicated that
female transgenic mice had significantly higher amounts of PRL than
female controls (P < 0.005), whereas male transgenic
mice showed no differences in PRL contents compared with male controls
(P = 0.4644). We also detected a main effect of gender
(P < 0.0001) and genotype (P < 0.05)
in TSH contents, but no interaction (P = 0.77) was
detected. TSH contents in transgenic mice were slightly lower than
those in normal controls in both genders. Gender differences were also
detected in GH and LH contents (P < 0.05 and
P < 0.0001, respectively). No differences in GH and LH
contents were detected between normal and transgenic mice
(P = 0.336 and P = 0.369,
respectively).
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). PRL gene expression was
elevated in female transgenic mice compared with that in female
controls (P < 0.05). No differences in PRL mRNA levels
were detected between normal and transgenic male mice. In contrast to
PRL, GH mRNA levels were not different in normal control and transgenic
mice (Fig. 6B). Gender differences in both PRL and GH gene expression
were detected (P < 0.05).
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) and male (Fig. 7B) mice were measured
by RIA. Three-way ANOVA revealed a significant main effect of gender
(P < 0.001). Female mice had significantly higher
levels of PRL than male mice. Despite the increase in PRL protein
contents and PRL gene expression in 2- to 4-month-old female transgenic
mice, plasma concentrations of PRL did not reach statistical
significance (P = 0.21) between female control and
transgenic mice at this age (Fig. 7A). Beginning at 6 months of age,
female transgenic mice had significantly higher levels of plasma PRL
than normal mice (P < 0.05). Changes were not detected
in plasma PRL concentrations in males between the different ages and
genotypes. Plasma GH concentrations were similar between the different
ages, genders, and genotypes (Table 2).
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) and
male (Fig. 8B) normal and transgenic mice at different ages. Three-way
ANOVA showed significant main effects of age (P <
0.001), gender (P < 0.005), and genotype
(P < 0.005). Female mice had significantly higher
numbers of pituitary cells than male mice. In female mice, two-way
ANOVA revealed significant effects of age (P < 0.001)
and genotype (P < 0.005). Female mice, 11–17 months
of age, had significantly greater numbers of pituitary cells than the
other two age groups examined (P < 0.05). Multiple
comparison analysis indicated that there was a significant increase in
cell number in 11- to 17-month-old female transgenic mice compared with
controls of the same age (P < 0.001). No differences
in cell numbers were detected between the different ages and genotypes
in males.
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;
P < 0.05). No changes in PRL gene expression at the
level of the individual cell were detected in males. There was a
significant effect of gender on PRL gene expression at the cellular
level (P < 0.001). The percentage of PRL-expressing
cells in the anterior pituitary of female transgenic mice was slightly
and significantly higher than in female controls (Fig. 9B;
P < 0.05). No differences in the percentage of
lactotrophs were detected between control and transgenic male mice.
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; P < 0.05). In
contrast, ovariectomy significantly decreased anterior pituitary
weights in female mice (Fig. 10; P < 0.05). In sham
controls, anterior pituitary weights were significantly higher in
transgenic mice compared with control values in both male and female
mice (P < 0.05). Estrogen treatment and ovariectomy
diminished the differences between normal and transgenic mice
(P < 0.05).
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). Estrogen treatment significantly
increased PRL secretion compared with that in sham controls in both
normal and transgenic male mice (P < 0.05). In
contrast, ovariectomy significantly decreased PRL secretion in both
normal and transgenic female mice (P < 0.05). In sham
controls, pituitary cells from transgenic female mice secreted higher
levels of PRL than those from normal controls (P <
0.05), and ovariectomy abolished this difference.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hyperprolactinemia and pituitary hyperplasia occurred only in female transgenic mice, and male transgenic mice showed no changes in PRL synthesis and secretion despite a dramatic 20- to 40-fold increase in galanin peptide in the anterior pituitary. These data suggest that estrogen is necessary for galanin-mediated increases in PRL production and pituitary growth. Although treatment with estrogen significantly increased PRL secretion and anterior pituitary weights in male mice, there were no differences between nontransgenic and transgenic male mice. Thus, in adult male transgenic mice estrogen and overexpression of galanin in the pituitary are not sufficient to induce the same degree of hyperprolactinemia and hyperplasia as that observed in females. The failure of male galanin transgenic mice, even those treated with estrogen, to develop a more profound pituitary hyperprolactinemia/hyperplasia than normal mice is reminiscent of the gender differences observed in the estrogen-hypersensitive Fischer-344 rat (21, 22). With regard to the development of hyperprolactinemia, pituitary cell hyperplasia, and galanin gene expression, male Fischer-344 rats are much less sensitive than females to the effects of estrogen. Thus, males appear to have gender-dependent and potentially estrogen-independent factors regulating the development of pituitary hyperplasia and hyperprolactinemia.
It is not readily apparent why male galanin transgenic mice did not show elevated PRL production. Galanin contents were significantly increased, and high levels of galanin peptide were released into cultured medium, suggesting that male transgenic mice had significantly higher local concentrations of galanin in the anterior pituitary that did not exert any dramatic effect on PRL synthesis and secretion. One possible explanation is that galanin receptors may be not expressed in lactotrophs in male mice. In addition, estrogen may up-regulate galanin receptor expression in the anterior pituitary, thus resulting in gender differences in the responsiveness to galanin. At least three galanin receptors have been characterized (23, 24, 25, 26), and, to date, the galanin receptor type 2 (GALR2) is primarily expressed in the anterior pituitary (27). However, no studies have been published to demonstrate the specific pituitary cell types that express GALR2. Moreover, the factors (e.g. estrogen) regulating GALR2 gene expression in the pituitary have not been explored.
Nontransgenic female mice with normal circulating levels of estrogen,
but much lower levels of pituitary galanin compared with transgenic
mice, have significantly lower levels of PRL production compared with
female transgenic mice. Furthermore, withdrawal of estrogen by
ovariectomy dramatically decreased PRL release and anterior pituitary
weights to a degree that was indistinguishable between normal and
transgenic mice. Recent data suggest that estrogen-induced galanin
production in the anterior pituitary is estrogen receptor dependent
(28). These results illustrate the key roles that galanin and estrogen
play in the formation of hyperprolactinemia and hyperplasia. Others
showed that female galanin knockout mice treated with estrogen showed
neither an elevation of PRL synthesis and release nor an increase in
pituitary cell numbers (29). Additionally, in vitro studies
showed that galanin antiserum abolishes the increase in PRL release
induced by treatment with estradiol (11, 14). Taken together, these
data indicate that estrogen is not the sole participant responsible for
the onset of hyperprolactinemia/pituitary hyperplasia in female mice.
Indeed, our studies suggest that galanin is essential in mediating
estrogen-induced pituitary hyperplasia, especially the proliferation of
lactotrophs.
The time course of the development of hyperprolactinemia and pituitary hyperplasia has a very interesting pattern. At 2–4 months of age, PRL synthesis, i.e. PRL content and gene expression, was increased in female transgenic mice. However, plasma PRL concentrations were not elevated until female transgenic mice reached the age of 6 months. It is possible that at younger ages, hypothalamic factors, such as dopamine, may inhibit PRL secretion in a compensatory manner to maintain plasma levels of PRL within a normal range (30). Dopamine appears to exert stronger inhibitory effects on PRL release than on PRL gene expression (31). Pituitary hyperplasia eventually occurred around 1 yr of age in female transgenic mice. Despite the important roles that galanin played, because the hyperprolactinemia occurred before pituitary hyperplasia we cannot rule out the possibility that PRL might also be acting as a growth factor. PRL may act as an autocrine growth factor through the activation of pituitary PRL receptors (32, 33, 34). Dopamine D2 receptor knockout mice showed a similar developmental pattern of hyperprolactinemia and pituitary hyperplasia (31, 35), which supports this idea. However, galanin gene expression has not been examined in dopamine D2 receptor knockout mice, and our previous studies showed that dopamine inhibits galanin gene expression (15).
Using the same PRL promoter, others generated transgenic mice
overexpressing nerve growth factor or transforming growth factor-
(TGF) in lactotrophs (33, 36). Both of these transgenic mouse models
reported the formation of hyperprolactinemia and pituitary hyperplasia.
Similar to our data, only female TGF transgenic mice developed
hyperprolactinemia and pituitary proliferation (36). Like galanin,
TGF is an autocrine factor that regulates PRL. However, male TGF
transgenic mice did not express detectable levels of TGF in the
pituitary, and the investigators believed that this was because the PRL
promoter was not activated in males. In our transgenic mice, the
galanin transgene was expressed in all three lines, demonstrating that
the PRL promoter is activated in both males and females. However,
female transgenic mice had significantly higher galanin peptide
contents and release than male transgenic mice. Therefore, the fragment
of the PRL promoter used appears more active in females than in males,
probably as a result of the compliment of transcription factors
(e.g. estrogen) (37). Both male and female nerve growth
factor transgenic mice developed pituitary hyperplasia, but similar to
the findings of our study, female transgenic mice showed a much more
dramatic lactotroph proliferation than male transgenic mice (33).
Another exciting discovery of this study was the formation of pituitary tumors in older female transgenic mice. Although only 20% of the hyperplastic pituitaries developed into pituitary tumors at about 1 yr of age, the percentage may increase with longer time of exposure to the high levels of pituitary galanin. Galanin also stimulates the proliferation of 235–1 cells, a rat pituitary tumor cell line (11). The mechanism by which galanin promotes tumor formation is not clear. Recent studies discovered that autocrine and paracrine factors play roles in certain cancer formation (38), and that galanin regulates PRL secretion in autocrine and paracrine manners (14). Also, galanin stimulates the growth of small cell lung cancer by mobilizing Ca2+, accumulating inositol phosphate (39).
Somatotrophs and lactotrophs share a common lineage (32). It is believed that somatotrophs first differentiate into mammosomatotrophs, then further differentiate into lactotrophs. Therefore, the differentiation of lactotrophs is dependent on somatotrophs. No changes were detected in GH synthesis (GH contents and GH mRNA levels) or secretion (plasma GH) in female transgenic mice despite the dramatic changes in lactotrophs. Therefore, the increase in the number of lactotrophs may be due to the postmitotic proliferation of lactotrophs. Overexpression of galanin in the anterior pituitary may not influence the lineage of somatotrophs or the differentiation of lactotrophs from somatotrophs. Instead, galanin may act as a growth factor to trigger and promote the proliferation of lactotrophs in the presence of estrogen. Further studies will be required to distinguish these possibilities. We also detected a decrease in TSH contents in transgenic mice that may be a result of a population shift.
In summary, overexpression of galanin in the anterior pituitary stimulates PRL synthesis and secretion in female mice and plays a key role in the process of hyperprolactinemia and pituitary hyperplasia. Galanin acts as a growth factor to promote the proliferation of pituitary cells, especially lactotrophs, in an estrogen-dependent manner.
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Acknowledgments |
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Footnotes |
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Received May 18, 1999.
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References |
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-dependent manner. Endocrinology 140:2628–2631 expression of
pituitary lactotrophs in transgenic mice results in selective
lactotroph proliferation and adenomas. Endocrinology 136:4479–4488[Abstract]
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