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Biocenter Oulu and World Health Organization Collaborating Center for Research on Reproductive Health, University of Oulu (P.N., H.P., M.M., P.V.), FIN-90014 Oulu; and the Department of Biosciences, Division of Biochemistry, University of Helsinki (P.V.), FIN-90014 Helsinki, Finland
Address all correspondence and requests for reprints to: Prof. Pirkko Vihko, Biocenter Oulu and World Health Organization Collaborating Center for Research on Reproductive Health, University of Oulu, P.O. Box 5000, FIN-90014 Oulu, Finland. E-mail: pvihko@whoccr.oulu.fi or pirkko.vihko{at}helsinki.fi
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Abstract |
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The results show that mouse 17HSD/KSR7 (m17HSD/KSR7) messenger RNA is distinctly and exclusively expressed in a proportion of corpora lutea (CLs). During pregnancy, expression of m17HSD/KSR7 is most abundant around embryonic day 14.5 (E14.5), when the ovaries are filled with CLs expressing 17HSD/KSR7. In the uterus, m17HSD/KSR7 is first detected on E5.5, when expression surrounds the implantation site on the antimesometrial side. As gestation progresses, m17HSD/KSR7 is expressed in the decidua capsularis on E8 and E9.5, disappearing thereafter from the antimesometrial decidua. On E9 onward, m17HSD/KSR7 messenger RNA expression takes place at the junctional zone of the developing placenta. On E12.5 and E14.5, m17HSD/KSR7 is abundantly expressed in the spongiotrophoblasts, where expression gradually declines toward parturition.
In conclusion, m17HSD/KSR7 expression in the CL is related to the life span of the CL. Moreover, spatial and temporal expression of m17HSD/KSR7 in the uterus suggests that locally produced E2 plays a role in implantation and/or decidualization. Finally, the results indicate that mouse placenta is capable of converting E1 to E2 in situ, and that the synthesized E2 may be effective in a paracrine, autocrine, and/or intracrine manner and be involved in placentation.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have recently cloned a novel type of 17HSD/KSR, type 7 (17HSD/KSR7), from mice (4). The corresponding protein has previously been cloned from rat tissue as PRL receptor-associated protein (PRAP), based on its capacity to bind the short form of PRL receptor (5). Similarly to mouse 17HSD/KSR7 (m17HSD/KSR7), rat PRAP was found to convert E1 to E2 efficiently; thus, we regard the protein as rat 17HSD/KSR7 (r17HSD/KSR7) (4). 17HSD/KSR7 is most abundantly expressed in corpora lutea (CLs) in the ovaries, particularly from embryonic day 8 (E8) of rodent pregnancy onward (4, 6, 7). Expression of 17HSD/KSR7 hence parallels E2 secretion from the corpus luteum (CL), and therefore, we suggest that 17HSD/KSR7 is the 17HSD/KSR enzyme needed for E2 biosynthesis in the CL (4). In the present study we demonstrate expression of 17HSD/KSR7 in the ovaries of nonpregnant and pregnant mice in detail using in situ hybridization.
A major difference between the functions of human and rodent placenta is in the biosynthesis of sex steroids. Rodent placenta synthesizes androgens as substrates for E2 biosynthesis in the CL, in contrast to human placenta, which is able to convert androgens further to E2 (8). At the same time, only limited amounts of progesterone (P) are secreted in rodent placentas, in contrast to human tissue (9). Rodent placenta has been assumed to be unable to synthesize E2 due to its lack of P450 aromatase (P450arom) (10, 11) and 17HSD/KSR1 (12, 13). Recent (4) and present results, however, indicate that 17HSD/KSR7 is also expressed in rodent placenta, which suggests that the reduction of estrone (E1) to E2 can also take place in placental cells. Using an in situ hybridization technique, we also show the expression of 17HSD/KSR7 in the mouse placenta during its development.
Finally, 17HSD/KSR7 is expressed in certain target tissues of estrogen action (4). We here demonstrate the cell-specific expression of m17HSD/KSR7 in the uterus during pregnancy, upon implantation in particular. Expression of 17HSD/KSR7 has been compared with that of 17HSD/KSR1, 17HSD/KSR2, and PRL-like protein B (PLP-B).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-35S]deoxy-CTP (1250
Ci/mmol) was purchased from NEN Life Science Products
(Boston, MA). Reagents used in the synthesis of riboprobes were
obtained from Promega Corp. (Madison, WI). Proteinase K
and transfer RNA were purchased from Roche Molecular Biochemicals (Mannheim, Germany). Autoradiography emulsion
NTB-2, developer D19 and fixer were obtained from Eastman Kodak Co. (New Haven, CT). Other reagents not mentioned in the text
were purchased from the Sigma (St. Louis, MO) or
Merck & Co. (Darmstadt, Germany) and were of the highest
purity grade available.
Tissue specimens
Formalin-fixed, paraffin-embedded NMRI mouse tissues were used.
Specimens from pregnant mice were collected from animals that had had a
vaginal plug in the morning following mating, and this moment was
considered embryonic day 0.5 (E0.5). Tissues were briefly washed with
PBS, fixed overnight in 4% paraformaldehyde-PBS, dehydrated, and
embedded in paraffin (Merck & Co.). Thereafter, 7-µm
sections were cut and collected on SuperFrost+
glass slides (Menzel-Glaser, Braunschweig, Germany). In
addition, 7-µm sections of conceptuses on E8 and E9 in the sagittal
plane of the animal (NIH Swiss strain, Novagen, Madison, WI) were
analyzed. Sections were dewaxed with xylene, and before hybridization,
reactive aldehyde groups remaining after fixation were eliminated by
10-min treatment with 0.1 M glycine/0.2 M
Tris-HCl, pH 7.4. For each analysis, duplicate samples were collected
from at least two independent series of mice. Representative series are
shown.
Cloning of mouse PLP-B (mPLP-B) and m17HSD/KSR7 complementary DNA
(cDNA) fragments for riboprobe preparation
Total and polyadenine-enriched RNAs were extracted from
placentas of pregnant mice (E11–13) using standard methods (14, 15). A
509-bp fragment of mPLP-B cDNA was transcribed from
polyadenine-enriched RNA using SuperScript II RT (Life Technologies, Inc., Gaithersburg, MD) and an antisense primer
that corresponds to nucleotides 693–674 of mPLP-B cDNA (16). The
fragment was then amplified with Pyrococcus furiosus
(pfu) polymerase (Stratagene, La Jolla, CA),
using the antisense primer () and the sense primer
corresponding to nucleotides 185–204 of the mPLP-B cDNA. The PCR
consisted of denaturation at 94 C for 1 min, annealing for 1 min at 60
C, and extension at 72 C for 2 min; the total number of cycles was
30.
A 499-bp fragment (nucleotides 351–849) of m17HSD/KSR7 was amplified with pfu polymerase using primers corresponding to nucleotides 351–376 and 849–831 of m17HSD/KSR7 cDNA (4). PCR cycles were identical to those described above. Both cDNA fragments were then cloned into Bluescript KS+ plasmid.
In situ hybridization
Sense and antisense
[-35S]deoxy-CTP-labeled m17HSD/KSR7 RNA
probes were transcribed with T3, T7, or SP6 RNA polymerases using
linearized plasmid as templates, according to the riboprobe in
vitro transcription system (Promega Corp.). A 499-bp
fragment (nucleotides 351–849) of m17HSD/KSR7 in Bluescript
KS+, a 737-bp fragment (nucleotides 584-1320) of
m17HSD/KSR2 in SP72 plasmid (17), a 403-bp fragment (nucleotides
1–403) of m17HSD/KSR1 in Bluescript KS+ (12),
and a 509-bp fragment (nucleotides 185–693) of mouse PLP-B cDNA in
Bluescript KS+ were used as templates to
transcribe m17HSD/KSR7, m17HSD/KSR2, m17HSD/KSR1, and PLP-B probes,
respectively. Specific activities of the RNA probes were 3–6 x
106 cpm/µl. The in situ
hybridization protocol was based on that described by Chotteau-Lelievre
et al. (18) with minor modifications described by Mustonen
et al. (17). Each section pair was hybridized with an
antisense and a sense probe. To visualize cells, sections were stained
with Hoechst 33258 or hematoxylin and eosin.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), whereas expression of
17HSD/KSR1 was demonstrated in the granulosa and cumulus cells of
developing follicles (Fig. 1H). A pronounced and constant 17HSD/KSR7
signal was observed in the CLs of nonpregnant (Fig. 1, A and I), E4.5
(data not shown), and E5.5 mice (Fig. 1J). In samples from E8.5 (Fig. 1, D and K) and E14.5 mice (Fig. 1, E and L), the signal for 17HSD/KSR7
messenger RNA (mRNA) in the CLs was also very intense. However, close
to parturition (E19), the signal was reduced (Fig. 1G) or occasionally
missing (data not shown) in pregnancy CLs.
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, I
and J,K). The CLs expressing 17HSD/KSR7 consisted mostly of normal
glandular epithelial cells with nuclei equal in size and pronounced and
pale-staining cytosol. The CLs expressing the type 7 enzyme were also
well vascularized, which is characteristic of an active CL. In
contrast, CLs lacking 17HSD/KSR7 had signs of regression; that is, they
had started to collapse or shrink, and the cells had pycnotic nuclei.
This was the case both in nonpregnant (Fig. 1B) and in pregnant mice on
E5.5 and E8.5 (data not shown). On E14.5, the ovaries were filled with
large CLs, which all expressed the enzyme (Fig. 1L). At that time,
there were also a few small CLs whose luteolysis and involution had
further progressed (Fig. 1F). These CLs were negative for 17HSD/KSR7
(data not shown).
Expression of m17HSD/KSR7 in the uterus and choriovitelline
placenta
No specific signal for 17HSD/KSR7 was detected in uteri of
nonpregnant or E4.5 mice (data not shown). In the uterus of E5.5 mice,
however, m17HSD/KSR7 was strikingly expressed in the stromal cells
surrounding the implantation site, on the antimesometrial side (Fig. 2, A and D). The expression was congruent
with that of mPLP-B, a marker protein for a decidual reaction (16, 19)
(Fig. 2B). In more detail, the area expressing mPLP-B and m17HSD/KSR7
represented the inner zone of the decidual reaction. Unlike mPLP-B and
m17HSD/KSR7, m17HSD/KSR2 was expressed in the endometrial layer of the
implantation site and not in the stromal decidual cells (Fig. 2C). Only
the antimesometrial region of the luminal epithelium, which is known to
be first subjected to degradation during the implantation process,
contained m17HSD/KSR2 mRNA.
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, F and G), but not for mPLP-B.
Similarly to E5.5 uterus, both m17HSD/KSR7 and mPLP-B were expressed in
the decidua on the antimesometrial side of E6.5 uterus, but only
m17HSD/KSR7 was present in the outer zone of the decidua (data not
shown). No specific signal for m17HSD/KSR7, m17HSD/KSR2, or mPLP-B was
detected in the area of stromal edema, myometrium, or uterine glands of
E5.5 and E6.5 uterus. No specific signal with sense probes was detected
in any part of the uterus (Fig. 2, E and G).
The decidual reaction results first in the formation of antimesometrial
decidual cells and then the formation of mesometrial decidual cells
around the developing conceptus. Expression of m17HSD/KSR7 continued in
the antimesometrial decidual layer, the decidua capsularis, in mice on
day E8 (Fig. 2H) and E9.5 (Fig. 2J). The expression level of
m17HSD/KSR7 on E9.5 was particularly high. After that, the signals for
m17HSD/KSR7 gradually disappeared and could no longer be detected in
the remnants of the deteriorating antimesometrial decidual layer on
E12.5 (data not shown). In the mesometrial decidual layer, a signal for
m17HSD/KSR7 could also been seen on E8, but on E9 it was
indistinguishable from the background (data not shown). The giant cells
surrounding the fetus did not show signals for m17HSD/KSR7 (Fig. 2, H
and J).
Expression of m17HSD/KSR7 in the developing and mature
chorioallantoic placenta
From E9 onward, m17HSD/KSR7 was also expressed in the spongy or
basal layer of the chorioallantoic placenta (Fig. 3B), similarly to mPLP-B, which was used
as a marker for spongiotrophoblasts (20). The expression of m17HSD/KSR7
was limited to the spongiotrophoblast layer of the junctional zone and
was not detected within the trophoblast giant cells that form the
boundary between the maternal and extraembryonal compartments.
Expression of m17HSD/KSR7 and mPLP-B reached up to the
spongiotrophoblasts in the peripheral margin of the placenta, but no
specific signal was seen in the giant cells there either (Fig. 3, C and
D). High expression of both m17HSD/KSR7 and mPLP-B was also seen in the
spongiotrophoblasts on E14.5, and the signal for both of the mRNAs was
also distinct in the pegs of spongiotrophoblasts, which penetrate into
the labyrinthine zone (Fig. 3, E, F, and H). On the other hand, Fig. 3, E, F, and G show how the expression of m17HSD/KSR2 was restricted to
the labyrinth zone on E14.5 and was opposite that of m17HSD/KSR7 and
mPLP-B. Expression of m17HSD/KSR7 continued on E17.5 in the narrowing
spongiotrophoblast layer and was especially pronounced in the
peripheral margin of the placenta (Fig. 3I). However, the expression of
mPLP-B had decreased, being barely detectable on E17.5 onward (Fig. 3J). On E19, expression of m17HSD/KSR7 had considerably decreased as
well (Fig. 3K).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The ovaries are an essential source of E2. Immunohistochemical (23, 24) and the present in situ hybridization experiments show that in both human and rodent ovaries, 17HSD/KSR1 is expressed in the granulosa and cumulus cells of developing follicles. After luteinization, 17HSD/KSR1 expression is down-regulated in the formed CL. Although expression of rat type 1 enzyme is reduced to an undetectable level (23, 25), expression of human 17HSD/KSR1 continues in the CL to some extent (24). Instead of the type 1 enzyme, abundant expression of 17HSD/KSR7 takes place in rodent CLs, in both nonpregnant (present study) and pregnant animals (Ref. 7 and the present study).
Only a fraction of CLs contained the 17HSD/KSR7 transcript in samples from nonpregnant, E5.5, and E8.5 mice. Histological differences between CLs containing and lacking 17HSD/KSR7 indicate that in nonpregnant mice the former are CLs of the current cycle, whereas the latter are from a previous cycle(s). Correspondingly, in pregnant mice, pregnancy CLs express 17HSD/KSR7, whereas CLs without the transcript are most likely from a previous cycle(s). After midpregnancy, on E14.5, for example, the ovaries are filled with large CLs, which all expressed 17HSD/KSR7. This is in agreement with the observation of abundant expression of the type 7 enzyme seen in Northern blot analyses (4, 6). At the same time there are a few small CLs that are negative for 17HSD/KSR7 and are increasingly regressed. These CLs are presumably from the cycle before pregnancy. The results thus suggest that 17HSD/KSR7 is expressed in most recently formed CLs and that the expression declines with luteolysis of CLs if pregnancy does not occur. In the case of pregnancy, expression of 17HSD/KSR7 continues in CLs throughout pregnancy, declining close to parturition. However, we cannot exclude the possibility that some CLs of the previous cycle are activated in midpregnancy to express the type 7 enzyme.
The present in situ hybridization analysis of uterine samples from pregnant mice also shows the distinct expression of 17HSD/KSR7 in the decidual reaction zone on E5.5 and E6.5; expression is more abundant in the inner than the outer zone. As pregnancy advances, the expression of 17HSD/KSR7 continues in the antimesometrial layer, being very abundant on day E9.5 and then disappearing along with the decline of the layer. Estrogen is known to play a crucial role in implantation, particularly in rodents (26). Together with P, it primes the uterus for implantation, nidatory estrogen triggers implantation, and E2 augments several effects of P on the decidual cell layer after implantation. Ovariectomy prevents implantation (27, 28), which cannot take place without systemic estrogen; thus, the local E2 biosynthesis possibly occurring in the uterus is not able to replace the ablation of ovarian estrogen. Switching on 17HSD/KSR7 expression between E4.5 and E5.5, however, suggests that the type 7 enzyme plays a role in implantation or immediately after that in the decidual reaction.
Mouse blastocysts ubiquitously contain estrogen receptor-, thus
being able to respond to maternal estrogen signal during and after
implantation (26, 29). 17HSD/KSR7 in the stromal cells surrounding the
implantation site may serve as an additional source of
E2, whereas 17HSD/KSR2 in the epithelial
endometrial cells may limit the access of excessive
E2 to the conceptus. More importantly, the action
of 17HSD/KSR7 may yield E2 for stromal cell
proliferation and differentiation into decidual cells in the first half
of pregnancy, when the E2 surge from the ovaries
is not maximal. In decidual cells, E2 together
with progestin modulates the expression of several genes suggested to
have a role in decidualization and mural trophoblast giant cell
invasion (30, 31, 32). E2-induced cell
proliferation is increased on the antimesometrial side of the
implantation site in particular (33, 34), concurrently with the
expression of 17HSD/KSR7. In contrast, uterine luminal epithelial cells
respond weakly to E2 treatment despite the
presence of ER (33), which is in agreement with the presence of
17HSD/KSR2 in the epithelial cells.
By E9, expression of 17HSD/KSR7 has started a shift from the antimesometrial decidual cells to the chorioallantoic placenta. A similar switch has been demonstrated in the expression of PLP-B (20). Characteristically, neither 17HSD/KSR7 nor PLP-B expression has been seen in giant cells at any stage of pregnancy, and expression of the proteins is limited to the spongiotrophoblast layer of the placenta. Expression of 17HSD/KSR2, in turn, takes place in both mural and polar giant cells and in spongiotrophoblasts in the junctional zone on E8 and E9, after which expression of the type 2 mRNA gradually shifts to the labyrinth zone (35). By E14.5, its expression has disappeared from giant cells and spongiotrophoblasts (Ref. 35 and the present study), and 17HSD/KSR2 and 17HSD/KSR7 show opposed expression in the labyrinth and junctional zone, respectively.
Because of a lack of P450arom, rodent placentas cannot synthesize estrogens from androgens, and the ovaries are the main source of E2 during rodent pregnancy (36). Accordingly, mouse placenta does not secrete estrogens in the classical endocrine manner, and in addition, the action of 17HSD/KSR2 may limit the entrance of E2, converted from E1, to the circulation (35). E2, synthesized by 17HSD/KSR7 in situ, may thus exert paracrine, autocrine, or even intracrine effects on the placenta. This is supported by a study showing that mouse trophoblasts contain estrogen receptors (37). Furthermore, treatment of pregnant rats on E9–E11 with an antiestrogen, tamoxifen, has been demonstrated to cause severe impairment of decidual development, which is associated with altered placental bed vascularization, deteriorated fetoplacental development, and increased incidence of growth-retarded fetuses and fetal death (38). Hence, estrogen action is needed to carry rodent placentation successfully to completion, and 17HSD/KSR2 and 17HSD/KSR7, which show precise cell-specific expression, may be needed in the placenta for accurate regulation of estrogen action.
Altogether, the results showed strict cell-specific expression of 17HSD/KSR7 in the ovaries, placenta, and uterus. In rodent ovaries, expression of 17HSD/KSR1 and 17HSD/KSR7 alternated in the follicles and CLs, respectively. The presence of two estrogenic and reductive 17HSD/KSRs in the ovaries may reflect a mechanism by which E2 production can be regulated cell specifically. In the placenta and uterus, 17HSD/KSR7 and 17HSD/KSR2 expressions were taking place in adjacent, but not in the same cells, in the specimens studied. The presence of 17HSD/KSR2 and 17HSD/KSR7 in the uterus and placenta may therefore reflect part of a system by which estrogen action is regulated in these tissues. In particular, the expression of 17HSD/KSR7 in decidual cells suggests that the enzyme plays a role in the regulation of E2 action in implantation and/or the decidual reaction.
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Acknowledgments |
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Footnotes |
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2 Present address: Orion Corp., Orion Pharma, P.O. Box 65, FIN-02101
Espoo, Finland.
Received July 27, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-3H,
progesterone-4-14C and
androstenedione-4-14C by rat placental tissue.
Endocrinology 87:151–155-hydroxysteroid dehydrogenase enzymes in
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