Absence of Dopaminergic Control on Melanotrophs Leads to Cushings-Like Syndrome in Mice
Adolfo Saiardi and
Emiliana Borrelli
Institut de Génétique et de Biologie Moléculaire
et Cellulaire Centre Nationale de la Recherche
Scientifique/INSERM/ Université Louis Pasteur BP 163 67404
Illkirch Cedex C.U. de Strasbourg, France
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ABSTRACT
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Dopamine negatively regulates POMC gene expression
in melanotrophs of the intermediate lobe of the pituitary gland. The
dopaminergic receptor involved in this control is the dopamine D2
receptor (D2R). The principal products of the POMC gene in melanotrophs
are ß-endorphin and
-MSH. POMC is differently processed in the
corticotrophs, where it is not regulated by dopamine and it is
principally processed into ACTH. Here we show that D2R-deficient mice
have increased POMC expression and intermediate lobe hypertrophy.
Strikingly, D2R-deficient mice have unexpected elevated ACTH levels
with a corresponding increase of corticosteroids and consequent
hypertrophy of the adrenal gland. This phenotype is reminiscent of
Cushings syndrome in humans. Interestingly, we show that the
elevation in ACTH levels is due to an aberrant processing of POMC in
melanotrophs. Indeed, we demonstrate that in addition to controlling
POMC gene expression in these cells, dopamine, by modulating the
expression of the convertases involved in the cleavage of the POMC
prohormone, strictly regulates its processing. These results reveal a
key role for dopamine in the control of POMC-derived peptides and
furthermore indicate an implication of the dopaminergic system in the
genesis of Cushings syndrome.
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INTRODUCTION
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In parallel to its functions in the central nervous system,
dopamine also exerts an inhibitory neuroendocrine control of hormone
synthesis and release in the pituitary gland (1, 2). The pathway
involved in such function is the tubero-infundibular pathway. The
effects of dopamine on pituitary cells are elicited through its
interaction with dopamine D2 receptors (D2Rs) (3). D2R is a member of
the seven-transmembrane domain G protein-coupled receptor family. The
best characterized signal transduction pathway of D2Rs is the
inhibition of adenylyl cyclase, which results in the decrease of
intracellular cAMP levels. In addition, other signal transduction
pathways have also been shown to be activated by this receptor (3). Two
distinct isoforms of D2R have been identified, D2L and D2S, issued from
alternative splicing of the same gene (4, 5). D2L and D2S present
similar pharmacological properties and anatomical distribution (6). In
the pituitary gland D2Rs are present on the membrane of lactotrophs and
melanotrophs (7) where it regulates the synthesis of PRL in lactotrophs
(2) and of the POMC gene products in melanotrophs (1, 8).
The regulation of the POMC gene transcription deserves special
attention in that it is differentially controlled in the two pituitary
cell types: the corticotrophs of the anterior lobe (AL) and the
melanotrophs of the intermediate lobe (IL). In both cell types POMC
synthesis is ensured by the hypothalamic corticotropin releasing factor
(CRF) (9, 10), whereas the negative control upon POMC expression is
ensured in a cell type-dependent manner. Indeed, down-regulation of
POMC transcription is controlled by glucocorticoids in the
corticotrophs (11) and by dopamine in the melanotrophs (8). This
differential control reflects the physiological specialization of the
two POMC-producing cell types. Corticotrophs are in fact the cells
devoted to the production of ACTH, which acts on adrenals to stimulate
corticosteroid synthesis (12). Corticosteroids, in turn, blunt POMC
expression in these cells by an inhibitory feedback loop. In contrast,
POMC in rodent melanotrophs produces essentially
-MSH and
ß-endorphin (ß-end), and it is inhibited by dopamine (13). ACTH,
-MSH, and ß-end derive from the cleavage of the POMC prohormone by
the activity of the prohormone convertases PC1 and PC2 (14, 15, 16). PC1 is
strongly expressed in corticotrophs and PC2 in melanotrophs (17). This
suggests that a strict cell-specific control of POMC transcription and
processing is required to keep normal physiological responses.
The generation of D2R-deficient mice (18) has allowed the study of the
involvement of this receptor in the control of pituitary gland
functions. Interestingly, loss of D2R expression leads to pituitary
hyperplasia of AL (19) due to an aberrant increase of PRL levels and
consequent overgrowth of lactotrophs. Thus, dopamine is an
antiproliferative signal for lactotrophs (19). At the melanotrophs
level we have found that lack of dopamine signaling via D2R results in
a striking enlargement of the IL. Thus, the antiproliferative effect of
dopamine is also observed at the level of the melanotrophs. This is in
support of the basic idea that lack of tonic inhibition on endocrine
cells, possibly mediated through the inhibition of the cAMP pathway,
leads to aberrant growth. In addition, here we show that, in the
absence of D2R, melanotrophs lose their cell identity and start to
produce ACTH. This aberrant production of ACTH leads to adrenal
hyperplasia. Taken together, these results indicate that absence of
dopaminergic control on melanotrophs leads to a Cushings-like
syndrome and suggest that dopamine deficiency might be one of the
causes of this disease in humans.
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RESULTS
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Lack of D2R Leads to POMC mRNA Increase and IL Hyperplasia
Histological analyses of the pituitary gland of D2R-null mice have
revealed a hyperplasia of the IL with a 40% increase of the number of
cells in the lobe (19). To better characterize these effects at the
cellular and molecular levels, we first performed an in situ
hybridization analysis (Fig. 1A
) using
the mouse POMC probe. As expected, a robust labeling of both the
corticotrophs in the AL and melanotrophs in the IL was obtained in the
pituitaries of wild-type (WT) and mutant mice. However, a 2-fold
increase in POMC mRNA expression was observed in the melanotrophs of
D2R-deficient mice as compared with WT siblings (Fig. 1
). In Fig. 1A
it
is also possible to appreciate that the enlargement of the IL in mutant
mice is due to the proliferation of POMC-producing cells (19).
Importantly, the observed increase of POMC expression is specifically
restricted to melanotrophs and does not extend to corticotrophs, as
shown by ribonuclease (RNAse) protection experiments in which we
separated the AL from the IL (Fig. 1B
). In agreement with the in
situ hybridization experiments, quantification of POMC mRNA
augmentation by RNAse protection demonstrates a 2-fold increase in
D2R-null mice as compared with WT animals using similar amount of RNA
(Fig. 1
, B and C). Thus, lack of D2R in the IL results in the
appearance of two phenomena, the first corresponding to an
up-regulation of POMC expression and the second to the proliferation of
melanotrophs.

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Figure 1. POMC Gene Expression in the Pituitary Gland of WT
and D2R -/- Mice
A, In situ hybridization using a mouse POMC antisense
RNA probe on sections from 4-month-old WT and D2R -/-mice
pituitaries. Scale bar, 75 µm. PL, Posterior lobe. B,
RNAse protection analysis of POMC mRNA in the AL and IL of WT and D2R
-/- mice. Histone H4 expression was used as internal control for RNA
quantity in each sample. Results are representative of three
independent experiments using different animals (n = 3). C,
Quantification of POMC mRNA expression in RNAse protection experiments
using D2R -/- mice and WT littermates. Values are expressed as
mean ± SD; quantification of the intensity of the
band corresponding to the WT was arbitrarily fixed to 100. **,
P < 0,01, unpaired Students t
test.
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D2R Knockout Does Not Affect Hypothalamic CRF Expression
It is well known that positive hypothalamic signals are needed to
induce synthesis and secretion of POMC-derived peptides (9).
Corticotropin-releasing factor (CRF), produced at the level of the
hypothalamic paraventricular nucleus, is the major releasing factor
acting on corticotrophs (11) and melanotrophs (11, 20). Thus, we
analyzed whether the increased size of the IL and POMC expression might
be secondary to an aberrant hypothalamic control over CRF expression.
In situ hybridization of D2R-null and WT brain sections
showed no differences in the expression of the CRF gene between the two
groups (Fig. 2
). This indicates that lack
of D2Rs does not affect the expression of the hypothalamic releasing
factor involved in the regulation of POMC synthesis. Consequently, CRF
does not seem to be directly involved in the generation of the IL
phenotype of D2R-null mice.

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Figure 2. In Situ Hybridization Analysis of
CRF mRNA Expression in the Hypothalamus of WT and D2R -/- Mice
A, Serial sections from the brains of WT and D2R -/- mice were
hybridized with a CRF antisense riboprobe. Similar results were
obtained in three independent experiments using different animals
(n = 3). PVN, Paraventricular nucleus. B, Quantification of CRF
mRNA expression in the hypothalamus of WT vs. D2R -/-
mice. Grain density/0.01 mm2 was measured in comparable
sections of three animals of each genotype in three different
experiments. Values are expressed as mean ± SD.
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Abnormal Increase of ACTH in D2R-Null Mice
Next we verified by RIA whether the increased expression of POMC
in D2R-null mice corresponded to a similar elevation of POMC-derived
hormones in the sera of these animals. In agreement with the mRNA
increase, the results of these analyses clearly showed that ß-end and
-MSH serum levels were increased 5.7- and 2.7-fold, respectively, in
mutant mice, as compared with WT controls (Fig. 3
). During quantification of POMC-derived
peptides, we also measured ACTH levels, which should have been not
affected in D2R-null mice. Strikingly, a 4-fold increase of this
hormone was measured in D2R-null mice with respect to control
littermates (Fig. 3
). This result was completely unexpected since
antagonism of D2R has never been shown to lead to ACTH increase. In
addition, ACTH is normally produced by the corticotrophs of the AL and
not by melanotrophs in normal pituitary glands. Indeed, it is well
established that corticotrophs do not express D2Rs and, in fact,
dopamine does not have inhibitory effects on these cells (12). In
agreement with this finding, both in situ and RNAse
protection analyses of POMC expression show an increase of this mRNA
only in RNAs extracted from the IL and not from the AL (Fig. 1
, A and
B). Thus, absence of dopaminergic control in the melanotrophs results
in an increase of all POMC-derived peptides and consequently in the
loss of melanotrophs cell specialization.

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Figure 3. Blood Levels of POMC-Derived Peptides in WT and D2R
-/- Mice
The number of animals used for the determination of each hormone is
indicated above the corresponding columns. Values are
means ± SD. **, P < 0.01,
unpaired Students t test.
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Cushings-Like Syndrome in D2R-Null Mice
POMC expression in corticotrophs is inhibited by glucocorticoids
as an adrenal feedback mechanism to reduce ACTH levels and consequently
steroids synthesis. In humans, Cushings syndrome refers to the
disorder caused by pituitary ACTH hypersecretion (21, 22) and
consequent glucocorticoid excess. In light of the observed increase of
ACTH levels in D2R-null mice, we analyzed the level of serum
corticosterone, the most abundant steroid in rodents, in WT and D2R
mutant animals. Interestingly, measurement of plasma corticosterone
levels in D2R-null vs. WT animals showed a significant
1.5-fold increase of this steroid (mean ± SD: WT,
290±150 ng/ml, n = 10; D2R -/-, 440 ± 250 ng/ml, n =
11; P < 0.05 Students t test). Chronic
ACTH hypersecretion in Cushings syndrome results in a
hyperstimulation of the adrenal cortex that leads to adrenocortical
hypertrophy and hyperplasia. Thus, we performed a histological analysis
of the adrenal glands of WT and D2R-null mice. We found a remarkable
enlargement of the adrenal cortex in glands from D2R-null animals, as
compared with WT mice. The histological analysis demonstrates the
presence of the characteristic fusion of the zona fasciculata and
reticularis (Fig. 4
), a feature known to
be present in patients with Cushings syndrome upon ACTH
overstimulation. In addition, D2R-null mice presented a
hyperpigmentation of their coat (data not shown) due to high
-MSH
and ACTH levels. Again, this is in line with the pathological signs of
Cushings syndrome.

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Figure 4. Adrenal Hypertrophy in D2R -/- Mice
Hematoxylin-eosin staining of adrenal serial sections from 4-month-old
WT (n = 3) and D2R -/- mice (n = 3). Zonae glomerularis
(G), fasciculata (F), and reticularis (R) are indicated. In the D2R
-/- section the fusion of the zonae fasciculata and reticularis is
evident.
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These results are of a remarkable medical interest since defects of the
dopaminergic system have never been associated with Cushings disease,
due to the knowledge that ACTH is normally not produced by melanotrophs
and that corticotrophs do not express D2Rs.
Overexpression of PC1 in the IL of D2R-Null Mice
Importantly, the pituitary cell-specific processing of the POMC
prohormone is ensured by two members of the furin family of proteases,
PC1 and PC2 (15, 16, 23). Notably, expression of the
melanotroph-specific PC2 convertase in AtT-20 cells, a
corticotroph-derived cell line, results in a POMC processing similar to
melanotrophs (15). To study the mechanism by which dopamine might
control POMC prohormone processing, we checked whether the expression
of PC1 and PC2 might have been altered in the pituitaries of D2R-null
mice. We thus analyzed the expression of these genes in WT and mutant
mice by in situ hybridization. In WT animals, PC1 expression
is mainly confined to the corticotrophs, while PC2 predominates in the
melanotrophs (Fig. 5A
) (17, 23). It was
previously reported that haloperidol treatment (a D2R antagonist) in
rats results in an increase in the pituitary expression of PC1 and PC2
(15, 16). Accordingly, the absence of the D2R in the mutant animals
provokes a 4- to 5-fold increase of PC1 expression in the melanotrophs
of these animals (Fig. 5B
). This result is consistent with the observed
ACTH serum level elevation in mutant animals (Fig. 3
). A 3- to 4-fold
increase in the expression of PC2 in melanotrophs is also observed in
D2R-null animals as compared with WT littermates (Fig. 5
).

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Figure 5. In Situ Analysis of PC1 and PC2 mRNA
Expression in the Pituitary Gland of WT and D2R -/- Mice
A, Serial sections from pituitaries of 4-month-old WT and D2R -/-
mice were hybridized with mouse PC1 and PC2 antisense riboprobes.
Results are representative of three independent experiments on three
different animals. Scale bar, 75 µm. B, Quantification
of the expression of PC1 and PC2 was performed as described in
Materials and Methods. Values are means ±
SD. **, P < 0,01, unpaired Students
t test.
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DISCUSSION
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Dopamine controls physiological functions both at the level of the
central nervous system (CNS) and of the pituitary gland. In the
pituitary, dopamine acts through the binding to D2Rs, which are
localized in two different cell types, the lactotrophs and the
melanotrophs. The best characterized function of dopamine on these
pituitary cells is the regulation of the synthesis and secretion of PRL
and POMC-derived peptides. The knockout of the dopamine D2R gene has
allowed a more detailed analysis of the dopaminergic control of
hormonal response and of general functions such as the control of cell
proliferation and identity. Indeed, absence of dopaminergic receptors
in the pituitary leads to aberrant proliferation of the lactotrophs,
which in older animals gives rise to tumors (19). This finding
indicates a more general function for dopamine in the neuroendocrine
system. Indeed, a neuromodulator can act outside of the CNS as a
maintenance factor for a particular cellular phenotype. Concomitant
with the increase of the PRL-producing cells we observed a decrease of
the cells that produce GH. These data are of interest since these two
cell types belong to a common cell lineage, and the somatotrophs appear
before the lactotrophs during pituitary development. Thus, dopamine
might act as a hypothalamic factor involved in the determination and
establishment of lactotroph identity.
This notion is strengthened by the phenotype of the IL of D2R-null
mice. Indeed, absence of D2Rs in the IL results in hyperplasia of
melanotrophs and in aberrant POMC expression and peptide processing.
Interestingly, lack of D2R has different impact on the proliferation of
the cells in the AL or IL. The hypertrophy and hyperplasia of the IL is
one of the clearest features of D2R-null pituitaries, even in young
animals (78 weeks old). By contrast, the hyperplasia of the AL is
delayed in time (34 months) but progressive, leading to tumors in
aged mice (19). The hyperplasia of the IL is instead contained, even in
aged animals. This is likely to be due to the different growth
characteristics of lactotrophs vs. melanotrophs. Indeed,
lactotrophs belong to a lineage more prone to proliferate under
specific stimuli, such as during pregnancy and lactation. It will be
important in future studies to assess whether the regulation of the
cell cycle might be different in lactotrophs vs.
melanotrophs.
The lack of dopaminergic control over POMC expression leads to an
increase in POMC-derived peptides. POMC is produced by two pituitary
cells, the corticotrophs in the AL, and the melanotrophs in the IL (9).
Despite the expression of the same gene, these two cell types differ in
the processing of the prohormone peptide, which results in a
specialization of the corticotrophs in the production of ACTH and of
the melanotrophs in that of
-MSH. Strikingly, the analysis of
D2R-null mice revealed an unexpected alteration of the processing of
the POMC propeptide in melanotrophs. There is a significant increase in
ACTH serum levels, due to an inappropriate expression of the convertase
PC1 in the IL of these mice. Thus, loss of D2R dramatically affects
both melanotroph cells proliferation and cellular identity, as shown
by the alteration of their normal hormone production. This leads to
animals with impaired endocrine responses. It is known that
melanotrophs do not express glucocorticoid receptors (24) and that ACTH
production cannot be fully controlled by the negative feedback loop of
corticosteroids on the pituitary, as happens in corticotrophs.
The adrenal phenotype exhibited by D2R-null mice is strikingly
reminiscent of Cushings syndrome (21, 22), showing the hypertrophy of
the adrenal cortex and the fusion of the zonae fasciculata and
reticularis. Interestingly, past reports described elevated ACTH levels
and Cushings syndrome in horses with IL pituitary tumors (25, 26);
unfortunately it is not known whether the dopaminergic system was
affected in these animals. Whether dopaminergic deregulation might
contribute to the genesis of human Cushings syndrome has not been
elucidated, because in humans the role of dopamine on POMC-producing
cells is not clear. The human pituitary lacks a well defined IL, and
the POMC-producing cells are intermingled with those of the
adenohypophysis. Importantly, earlier studies have shown that dopamine
agonists lower ACTH in some, but not all, Cushings syndrome patients
(27). Thus, dopamine might contribute, in some cases, to the etiology
of this disease in humans.
In conclusion, this study shows that dopamine has a key role outside
the CNS. It is involved in the regulation of hormone synthesis and
secretion, but most importantly in the control of cell proliferation
and in the maintenance of the melanotroph phenotype.
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MATERIALS AND METHODS
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Mice
D2R mutant animals were generated and identified by genomic
Southern blot analysis (18). All animals used in the experiments had a
mixed 129SVxC57Bl/6 genetic background, with a 75% contribution of
C57Bl/6 background; the WT mice used were littermates of D2R-null mice.
Animals were bred under standard animal housing conditions, in a 12-h
light/12-h dark cycle. Food and water were available ad
libitum. All experiments were conducted in conformity with the
French publication on animal experimentation (No. 87848) and the
European Communities Council Directive of November 1986
(86/609/EEC).
Histological Analyses
Adrenals from WT and D2R-deficient mice were fixed in Bouins
fixative for at least 1 day and embedded in paraffin. Serial microtome
sections (10 µm) were stained by hematoxylin-eosin. Three animals of
each genotype were analyzed.
In Situ Hybridization
WT and mutant mice were killed by decapitation after Rompun
(Bayer AG, Leverkusen, Germany) anesthesia. Brains and pituitaries were
rapidly removed and frozen in dry ice after embedding in Tissue Tek
O.C.T. compound (Sakura Finetek USA, Inc., Torrance, CA). Cryostat
sections (10 µm) were thaw-mounted on gelatin-coated slides and
stored at -80 C. Before hybridization, sections were rinsed in
ice-cold acetone, fixed in 4% formaldehyde, and washed in PBS.
Finally, slices were acetylated for 10 min in 0.0265 M
acetic anhydride/0.1 M triethanolamine to reduce
background, washed in 1x saline sodium citrate (SSC), incubated for 10
min at 60 C in 50% formamide, 1x SSC, and dehydrated. Sections were
hybridized overnight at 52 C with 35S-labeled antisense
riboprobes specific for pituitary markers in hybridization buffer (300
mM NaCl, 20 mM Tris-Cl, pH 7.5, 10% dextran
sulfate, 1x Denhardts solution, 5 mM EDTA, pH 8.0, 10
mM Na2PO4, pH 7.0, 50% formamide,
0.5 mg/ml yeast tRNA, 10 mM dithiothreitol). After
hybridization, sections were washed twice for 1 h at 55 C in 50%
formamide, 2x SSC and treated for 30 min at 37 C with RNAase A (20
mg/ml in 4x SSC). Sections were then extensively washed at 55 C under
increasing stringency up to 0.1x SSC and dehydrated in graded
ethanols. For autoradiography, dried sections were first exposed to
Kodak XAR-OMAT films and subsequently dipped in Kodak NTB2 nuclear
emulsion. Slides were exposed at 4 C for 14 days, developed, and
counterstained with toluidine blue. The specificity of the in
situ hybridization results was confirmed by the use of sense
strand riboprobes that showed no detectable signals (results not
shown). Experiments were analyzed using a Hamamatsu camera (Hamamatsu
Photonic Systems, Bridgewater, NJ) with a controller C2400; data were
quantified using an Imaging Technology 151 System (Hamamatsu Photonic
System, Bridgewater, NJ). The reported increase in POMC, CRF, PC1, and
PC2 were obtained by measuring grains density/0.01 mm2 in
1015 different areas of the analyzed tissue in at least three
independent experiments using different animals (n = 3). Data were
analyzed by the Students t test.
RNAse Protection
Total RNAs were prepared from the AL and IL by the LiCl method
(28). RNAse protections were performed as described (28). Three animals
of both sexes and genotypes were used in three independent experiments.
Equal amounts of RNA (0.1 µg for the IL and 0.2 µg for the AL) were
hybridized overnight at 45 C with a molar excess of
32P-labeled mouse POMC and H4 histone riboprobes. Samples
were treated with RNAase A (40 µg/ml) and T1 (2 µg/ml), incubated
with Proteinase K (150 µg/ml), extracted with phenol-chloroform, and
precipitated with ethanol. Protected fragments were run on a 6%
polyacrylamide/8 M urea gel. Autoradiograms were analyzed
and data quantified using a Bio-Rad GS-700 Imaging Densitometer
(Bio-Rad, Hercules, CA).
Hormone Analysis
Blood samples were collected from decapitated animals and
centrifuged at 4000 rpm for 15 min in an Eppendorf microfuge. Sera were
then removed and stored at -20 C. Hormone levels in serum samples were
determined by RIA; each determination was always performed in parallel
on both test populations (D2R-null mice and WT littermates), and the
results were deduced from their comparison. ACTH, ß-end, and
-MSH
were measured by RIA kits from Peninsula Laboratories, Inc. (Belmont,
CA) and corticosterone by an ICN Biomedical (Costa Mesa, CA) kit. The
ACTH kit has 0% cross-reactivity for
-MSH, LH-RH, PACAP 138, and
ß-end. The ß-end kit has 0% cross-reactivity for ACTH,
Met-Enkephalin,
-MSH, and PACAP 38. The
-MSH kit has 0%
cross-reactivity for ß-end,
-endorphin,
-endorphin,
Met-Enkephalin, and 0.02% ACTH (human). EDTA and aprotinin were added
to the blood samples following manufacturers suggestions. One hundred
microliters of serum were used for the
-MSH assay; 20 µl were used
for the ß-end and ACTH tests; 10 µl were used for corticosterone
evaluation. Statistical analysis was performed by unpaired Students
t test.
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ACKNOWLEDGMENTS
|
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We acknowledge Drs. P. Sassone-Corsi, Yuri Bozzi, Tarek A.
Samad, and members of the laboratory for discussions and critical
reading of the manuscript. We thanks Drs. K. E. Mayo (Northwestern
University, Evanston, IL), E. Jansen (Leuven, Belgium), and C.
Mazzucchelli for cDNA probes. We are grateful to V. Giroult for
technical assistance, T. Ding for paraffin sections, S. Falcone for
animal care, B. Boulay and J. M. Lafontaine for artwork, and to
J.-L. Vonesch for quantification of the in situ data.
 |
FOOTNOTES
|
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Address requests for reprints to: Emiliana Borrelli, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre Nationale de la Recherche/INSERM/Université Louis Pasteur, BP163, 67404 Illkirch Cedex, C.U. de Strasbourg, France. E-mail:
eb{at}igbmc.u-strasbg.fr
A.S. was supported by fellowships from the European Economic Community
and Fondation pour la Recherche Médicale. This work was supported
by funds from Centre Nationale de la Recherche Scientifique, Institut
Nationale de la Santé et de la Recherche Médicale,
Hôpital Universitaire de Strasbourg, and from a grant from the
Association pour la Recherche sur le Cancer to E.B.
Received for publication December 5, 1997.
Revision received March 31, 1998.
Accepted for publication April 13, 1998.
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REFERENCES
|
---|
-
Chen CL, Dionne FT, Roberts JL 1983 Regulation of the
pro-opiomelanocortin mRNA levels in rat pituitary by dopaminergic
compounds. Proc Natl Acad Sci USA 80:22112215[Abstract]
-
Elsholtz HP, Lew AM, Albert PR, Sundmark VC 1991 Inhibitory
control of prolactin and Pit-1 gene promoters by dopamine. Dual
signaling pathways required for D2 receptor-regulated expression of the
prolactin gene. J Biol Chem 266:2291922925[Abstract/Free Full Text]
-
Picetti R, Saiardi A, Abdel-Samad T, Bozzi Y, Baik JH,
Borrelli E 1997 Dopamine D2 receptors in signal transduction and
behavior. Crit Rev Neurobiol 11:121142[Medline]
-
Montmayeur JP, Bausero P, Amlaiky N, Maroteaux L, Hen R,
Borrelli E 1991 Differential expression of the mouse D2 dopamine
receptor isoforms. FEBS Lett 278:239243[CrossRef][Medline]
-
Jackson DM, Westlind-Danielsson A 1994 Dopamine receptors:
molecular biology, biochemistry and behavioural aspects. Pharmacol Ther 64:291370[CrossRef][Medline]
-
Montmayeur JP, Guiramand J, Borrelli E 1993 Preferential
coupling between dopamine D2 receptors and G proteins. Mol Endocrinol 7:161170[Abstract]
-
Autelitano DJ, Snyder L, Sealfon SC, Roberts JL 1989 Dopamine
D2-receptor messenger RNA is differentially regulated by dopaminergic
agents in rat anterior and neurointermediate pituitary. Mol Cell
Endocrinol 67:101105[CrossRef][Medline]
-
Cote TE, Felder R, Kebabian JW, Sekura RD, Reisine T,
Affolter HU 1986 D-2 dopamine receptor-mediated inhibition of
pro-opiomelanocortin synthesis in rat intermediate lobe. Abolition by
pertussis toxin or activators of adenylate cyclase. J Biol Chem 261:45554561[Abstract/Free Full Text]
-
Lundblad JR, Roberts JL 1988 Regulation of
proopiomelanocortin gene expression in pituitary. Endocr Rev 9:135158[Medline]
-
Meunier H, Lefevre G, Dumont D, Labrie F 1982 CRF stimulates
alpha-MSH secretion and cyclic AMP accumulation in rat pars intermedia
cells. Life Sci 31:21292135[CrossRef][Medline]
-
Beyer HS, Matta SG, Sharp BM 1988 Regulation of the messenger
ribonucleic acid for corticotropin-releasing factor in the
paraventricular nucleus and other brain sites of the rat. Endocrinology 123:21172123[Abstract]
-
Vale W, Vaughan J, Smith M, Yamamoto G, Rivier J, Rivier C 1983 Effects of synthetic ovine corticotropin-releasing factor,
glucocorticoids, catecholamines, neurohypophysial peptides, and other
substances on cultured corticotropic cells. Endocrinology 113:11211131[Abstract]
-
Pardy K, Carter D, Murphy D 1990 Dopaminergic mediation of
physiological changes in proopiomelanocortin messenger ribonucleic acid
expression in the neuroin-termediate lobe of the rat pituitary.
Endocrinology 126:29602964[Abstract]
-
Eipper BA, Mains RE 1980 Structure and biosynthesis of
pro-adrenocorticotropin/endorphin and related peptides. Endocr Rev 1:127[Medline]
-
Bloomquist BT, Eipper BA, Mains RE 1991 Prohormone-converting
enzymes: regulation and evaluation of function using antisense RNA. Mol
Endocrinol 5:20142024[Abstract]
-
Day R, Schafer MKH, Watson SJ, Chretien M, Seidah NG 1992 Distribution and regulation of the prohormone convertases PC1 and PC2
in the rat pituitary. Mol Endocrinol 6:485497[Abstract]
-
Zhou A, Bloomquist BT, Mains RE 1993 The prohormone
convertases PC1 and PC2 mediate distinct endoproteolytic cleavages in a
strict temporal order during proopiomelanocortin biosynthetic
processing. J Biol Chem 268:17631769[Abstract/Free Full Text]
-
Baik J-H, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis
A, Le Meur M, Borrelli E 1995 Parkinsonian-like locomotor impairment in
mice lacking dopamine D2 receptor. Nature 377:424428[CrossRef][Medline]
-
Saiardi A, Bozzi Y, Baik JH, Borrelli E 1997 Antiproliferative
role of dopamine: loss of D2 receptors causes hormonal dysfunction and
pituitary hyperplasia. Neuron 19:115126[Medline]
-
Lugo DI, Pintar JE 1996 Ontogeny of basal and regulated
proopiomelanocortin-derived peptide secretion from fetal and neonatal
pituitary intermediate lobe cells: melanotrophs exhibit transient
glucocorticoid responses during development. Dev Biol 173:110118[CrossRef][Medline]
-
Cushing H 1932 The basophil adenomas of the pituitary body and
their clinical manifestations. Bull Johns Hopkins Hosp 50:137142
-
Baxter JD, Tyrrell JB 1987 The adrenal cortex. In: Felig P,
Baxter JD, Broadus AE, Frohman LA (eds) Endocrinology and Metabolism,
ed 2. McGraw-Hill, New York, pp 247337
-
Seidah NG, Day R, Marcinkiewicz M, Benjannet S, Chretien M 1991 Mammalian neural and endocrine pro-protein and pro-hormone
convertases belonging to the subtilisin family of serine proteinases.
Enzyme 45:271284[Medline]
-
Antakly T, Mercille S, Cote JP 1987 Tissue-specific
dopaminergic regulation of the glucocorticoid receptor in the rat
pituitary. Endocrinology 120:15581562[Abstract]
-
Orth DN, Nicholson WE 1982 Bioactive and immunoreactive
adrenocorticotropin in normal equine pituitary and in pituitary of
horses with Cushings disease. Endocrinology 111:559563[Abstract]
-
Wilson MG, Nicholson WE, Holscher MA, Sherrel BJ, Mount CD,
Orth DN 1982 Proopiomelanocortin peptides in normal pituitary,
pituitary tumors and plasma of normal and Cushings horses.
Endocrinology 110:941954[Abstract]
-
Lamberts SWJ, Klijn JGM, De Quijada M, Timmermans HAT,
Uitterlinden P, De Jong F, Birkenhäger JC 1980 The mechanism of
suppressive action of bromocriptine on adrenocorticotropin secretion in
patients with Cushings disease and Nelsons syndrome. J Clin
Endocrinol Metab 51:307311[Medline]
-
Sambrook J, Fritsch EF, Maniatis T 1989 Molecular CloningA
Laboratory Manual, ed 2. Cold Spring Harbor Laboratory Press, Cold
Spring Harbor, New York