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REPRODUCTION-DEVELOPMENT |
Department of Veterinary Biosciences (T.S., P.S.C.) and Division of Nutritional Sciences (P.S.C.), University of Illinois, Urbana, Illinois 61802; Departments of Anatomy (T.K., G.R.C.) and Urology (G.R.C.), University of California, San Francisco, California 94143; and The Population Council (G.W., M.P.H.), Center for Biomedical Research, New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Paul S. Cooke, Department of Veterinary Biosciences, 2001 South Lincoln Avenue, University of Illinois, Urbana, Illinois 61802. E-mail: . p-cooke{at}uiuc.edu
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Introduction |
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Extensive data accumulated over the past few years suggest that locally produced, rather than systemic, IGF-I may be critical for uterine growth and E2 response. Yakar et al. (5) reported that mice lacking IGF-I production in their liver had 75% reductions in serum IGF-I, but grew and reproduced normally. The researchers interpreted these results as indicating the primacy of local, rather than systemic, IGF-I production for promoting the growth of various organs and tissues. Similarly, mice lacking the acid-labile subunit gene had over a 60% reduction in circulating plasma IGF-I, but normal local IGF-I production (6). These mice showed only a 10% reduction in body weight and were fertile. Indeed, Le Roith and colleagues (7) recently suggested that the primary effect of circulating IGF-I might not be growth but, rather, systemic negative feedback on GH secretion.
In contrast to data suggesting that systemic IGF-I may be superfluous, numerous reports suggest that locally produced IGF-I may be critical for E2-induced uterine responses. IGF-I protein and mRNA are produced in relatively high amounts in the uterus, E2 is the primary regulator of uterine IGF-I mRNA and protein production, and E2 also stimulates IGF-I receptor mRNA expression (1, 8, 9). Consistent with these data, the expression of IGF-I mRNA and IGF-I receptor varied during the estrous cycle in rat uterus, further suggesting E2 regulation of IGF-I production and response (10, 11).
Mitogenic effects of E2 on uterine epithelium are mediated indirectly through E2 binding to ER
in stroma (12), which leads to epithelial proliferation through an unknown mechanism probably involving paracrine effects of stromal growth factors (13). Some investigators have proposed that IGF-I could be a critical mediator of E2-induced stromal-epithelial interactions. IGF-I is produced either predominately (14) or exclusively (2) in stroma, and IGF-I receptor expression has been shown to be predominately in uterine epithelium using both in situ hybridization and immunohistochemistry (2, 15). Pierro et al. (16) reported that E2 increased epithelial proliferation in cocultures of human uterine stromal and epithelial cells, but had no mitogenic effect on epithelium alone. In addition, immunoneutralization of IGF-I in cocultures abrogated the effects of E2 on epithelial proliferation. Thus, evidence from several experimental approaches is consistent with the hypothesis that E2 induces local IGF-I production by uterine stroma, which may then act in a paracrine fashion on uterine epithelial IGF-I receptors to induce mitogenesis.
In this report we used IGF-I KO mice and a grafting strategy to test the roles of systemic and local IGF-I production in the uterine response to E2. Our results indicate that systemic IGF-I alone is sufficient for normal uterine growth and E2-induced uterine epithelial mitogenesis even in the absence of local IGF-I production. This suggests that increases in local uterine IGF-I production in response to E2 are not obligatory for normal uterine growth or epithelial proliferation, and also indicates that systemic IGF-I may be more critical for uterine growth and E2 response than previously realized.
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Materials and Methods |
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Tissue grafting
Uteri were removed from adult (60- to 90-d-old) WT and KO mice or neonatal (0- to 3-d-old) WT mice that had been killed by CO2 asphyxiation. Uteri were photographed, then one uterine horn was transplanted under the renal capsule of intact adult female athymic mice (Harlan Sprague Dawley, Inc., Indianapolis, IN). At the end of the 4-wk growth period, grafts were removed, weighed, photographed, and examined histologically.
Initial experiments involved grafting of WT or KO uteri into athymic female hosts to eliminate the possibility of tissue rejection while exposing the grafts to normal levels of circulating IGF-I. It was also of interest to compare the growth of WT or KO uteri in KO hosts lacking circulating IGF-I. However, even though the IGF-I KO colony had been inbred for several generations, these animals originally were derived from a mixed genetic background, and it was therefore unclear whether it would be possible to graft tissue from WT mice into WT or KO hosts without tissue rejection. Initial results indicated that WT uteri could be grown for extended periods of time under the kidney capsules of other WT hosts without obvious signs of tissue rejection. Therefore, subsequent experiments also involved WT uteri grown under the renal capsule of either WT or KO hosts for 4 wk.
Measurement of epithelial labeling index and mitotic rate
To determine the effects of acute E2 treatment on epithelial proliferation and expression of E2-dependent uterine epithelial secretory proteins, some athymic hosts were ovariectomized 4 wk after grafting. Ten days after ovariectomy, the hosts were given one injection of 125 ng E2 (Sigma, St. Louis, MO) in 0.05 ml corn oil or corn oil alone, and grafted uteri were harvested 18 h after E2 or oil treatment. To assess uterine epithelial proliferation in the grafts, we used both a colchicine block to determine the mitotic rate and [3H]thymidine autoradiography to assess the labeling index (LI). A single injection of 100 µg/20 g body weight (BW) colchicine (Sigma) dissolved in 0.2 ml saline solution was given 5 h before sacrifice to allow identification of mitotic figures. For thymidine autoradiography, [3H]thymidine (specific activity, 80 Ci/mmol; 1 Ci = 37 GBq; Amersham Pharmacia Biotech, Arlington Heights, IL) at a dose of 2 µCi/g BW was injected 2 h before death. Mice were killed by CO2. Uteri and grafted uteri were removed and fixed in 4% paraformaldehyde in PBS for 3–12 h at 4 C for thymidine autoradiography and/or PR immunohistochemistry or in Bouin’s solution for 24 h at room temperature for lactoferrin (LF) immunohistochemistry, then all tissues were paraffin embedded, and sectioned at 4 µm.
For [3H]thymidine autoradiography, mounted tissue sections were deparaffinized, dried, dipped in Kodak NTB-2 nuclear emulsion (Kodak, Rochester, NY), and stored at 4 C for 3–4 wk until sufficient labeling could be detected. Autoradiograms were developed by standard techniques, and slides were stained with hematoxylin and eosin. Epithelial LI of the various uterine grafts was measured as [3H]thymidine-labeled epithelial cells per total epithelial cells as described previously (12). A total of 4 KO and 3 WT grafts were used to quantitate LI. For each sample, a minimum of 600 epithelial cells were scored. Data on epithelial proliferation in various groups were analyzed by t test, and means were considered different at P 
0.05. For determination of the mitotic rate, mitotic figures were counted in a minimum of 600 epithelial cells for the same uteri that were used for LI determination.
Effects of E2 treatment on uterine weight and epithelial height of KO mice
The KO mice have decreased circulating E2 levels in addition to lacking IGF-I (2). Thus, to determine whether the decreased uterine size and uterine epithelial height in these mice resulted solely from the absence of IGF-I in these animals or from both the lack of IGF-I and the decreased E2 levels, intact adult (60- to 90 d-old) KO mice received daily injections of E2 (125 ng/25 g BW) for up to 14 d. Uteri were then harvested, weighed, photographed, and used for determination of uterine epithelial height.
Role of IGF-I in uterine protein expression
To determine whether the presence or absence of IGF-I affected the normal E2-induced changes in expression for PR and the uterine epithelial secretory protein LF, we used immunohistochemistry to examine the expression of these proteins in grafted adult WT and KO uteri and in uteri of KO mice before or after 14 d of E2 treatment. For LF immunohistochemistry, sections were deparaffinized and hydrated. Sections were washed three times in PBS, pH 7.4 (Sigma), and endogenous peroxidase activity was blocked by immersing the sections in 0.3% H2O2 in methanol for 30 min, followed by washing in PBS. Nonspecific binding was blocked using the Histostain-SP kit (Zymed Laboratories, Inc., South San Francisco, CA). Sections were then incubated with anti-LF antiserum obtained from Dr. Christina Teng (NIEHS) or normal rabbit serum for 1 h at room temperature. After washing with PBS, sections were incubated with a biotinylated second antibody from the Histostain-SP kit for 15 min at room temperature and visualized using the Histostain-SP kit according to the manufacturer’s protocol.
PR immunohistochemistry was performed as described previously by Kurita et al. (17). Briefly, paraformaldehyde-fixed paraffin sections (4 µm) were stained using anti-PR (DAKO Corp., Carpinteria, CA), followed by biotinylated donkey antirabbit Ig (Amersham Pharmacia Biotech). Signal was visualized with streptavidin conjugated to horseradish peroxidase (DAKO Corp.) and diaminobenzidine (Sigma) as the chromagen.
Image and data analysis
All images were captured using an Olympus Corp. (New Hyde Park, NY) Vanox photomicroscope with planapochromatic lenses or an Olympus Corp. dissecting microscope and a SPOT Cooled Color Digital Camera (Diagnostic Instruments, Sterling Heights, MI) interfaced to a Macintosh computer using Adobe Photoshop software (Adobe Systems, San Jose, CA). Epithelial height was measured using the NIH Image computer software program (Wayne Rasband, NIH, Bethesda, MD). Data were analyzed using a t test or Welch’s test, and differences were considered significant at P < 0.05.
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Results |
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). For grafts of adult WT uteri, wet weights at the time of recovery were actually decreased compared with weight at grafting. Most likely this resulted from focal necrosis in these uteri after grafting due to their large size and the time it takes for the graft to establish a blood supply; this is frequently seen when grafting large pieces of tissue. Both the neonatal WT and adult KO uterine tissue increased dramatically in size and weight over the 4-wk growth period (Figs. 1 and 2), typically showing increases of 20- to 30-fold in wet weight. At recovery, the wet weight of grafted neonatal WT or adult KO uterine horns equaled or exceeded that of adult WT uterine horns.
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). After grafting into athymic hosts, epithelial cell height in KO uterine grafts was increased (P < 0.05) to approximately equal that of grafted WT uteri.
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and 5) and did not differ between KO and WT grafts. The mitotic index was also high and was similar in the epithelium of adult WT and KO uterine grafts exposed to E2 (12–17%; Figs. 4 and 5).
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), and uterine epithelial height in the E2-treated KO mice was similar to that in WT or KO uterine grafts from normal athymic mice (Fig. 3
). Uterine wet weight in KO mice after the 3- or 14-d E2 treatment was 1.5- and 3-fold, respectively, that in control KO mice before injection (Fig. 6). Despite this increase, uterine size in KO mice after the treatment period was only approximately 10% that of pregrafting adult WT uterus, and the magnitude of the increase induced by E2 in KO mice was far less than the relative and absolute increases in uterine weight after E2 injection of ovariectomized WT mice (18). Therefore, although E2 restored epithelial height and caused some weight increase in KO uteri, the muted growth response of the KO uterus even after extended E2 treatment compared with the WT uterus indicates that the decreased size in KO uterus predominately reflects the lack of IGF-I.
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), probably as a result of reduced circulating E2 in these animals. PR expression in uteri of intact KO mice treated for 14 d with E2 (Fig. 7B) was similar to that seen for the WT and KO grafts, with low epithelial and high stromal PR expression. LF was expressed in uterine epithelium of WT and KO grafts grown in intact athymic hosts (not shown). Similarly, LF staining was minimal in uteri from intact KO mice before E2 treatment (Fig. 7C), but LF expression was observed in uteri of intact KO mice that received E2 injections for 14 d (Fig. 7D). Thus, whereas KO uteri do not show normal uterine growth or epithelial proliferation in response to E2, the characteristic uterine changes in both LF and PR expression induced by E2 do not require the presence of IGF-I.
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Discussion |
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We and others have shown that neonatal murine uterine tissue grafted under the renal capsule of host mice grows, differentiates, and shows normal responses to E2 and progesterone in terms of epithelial proliferation, secretory protein production, and ER and PR expression (12, 17, 20, 21). In the present study we have used this model system to examine the growth of WT and KO uteri in various types of hosts and endocrine environments to shed light on the roles of local and systemic IGF-I in E2-induced uterine growth.
Our results indicate that grafted KO uteri grow rapidly and reach the size of adult WT uteri when exposed to normal systemic levels of IGF-I in athymic hosts. In addition, there is no difference in epithelial LI and mitotic rate in KO and WT uteri grafted in ovariectomized athymic hosts treated with E2, and epithelial LI in these KO grafts is very similar to those previously reported for uterine epithelial LI in E2-treated ovariectomized mice (22). These results show that local IGF-I production is not necessary to support normal uterine growth and E2-induced epithelial mitogenesis, because these occur normally in an environment containing only systemic IGF-I.
Although local uterine IGF-I is not required for E2-induced uterine growth or epithelial proliferation, this does not preclude the possibility that local uterine IGF-I and systemic IGF-I may comprise a redundant signaling mechanism that induces uterine growth and epithelial proliferation in response to E2 in vivo. Due to this possible redundancy, the absence of local IGF-I production would not preclude or even impair uterine epithelial proliferation in response to E2 when adequate levels of systemic IGF-I are present. Therefore, the local uterine increases in IGF-I may contribute to E2 effects on uterine growth and epithelial proliferation in vivo, but they are not necessary.
The uterine hypoplasia in KO mice preferentially reflects the lack of IGF-I rather than E2, because even extended E2 treatment cannot restore normal uterine growth. Our results confirm earlier observations of Adesanya et al. (3), who reported that E2 treatment of KO mice did not induce uterine epithelial proliferation because these cells could not transit the G2 phase of the cell cycle without IGF-I. Therefore, IGF-I is necessary for normal uterine growth and E2-induced epithelial proliferation. In contrast to uterine growth, E2 replacement to KO mice restores uterine epithelial height to normal, showing that reduced E2 in KO mice, rather than the absence of IGF-I, is responsible for decreased uterine epithelial height in KO uteri in vivo.
The KO uteri were able to produce LF and show typical changes in their pattern of PR expression in response to E2. The production of LF in mouse uterine epithelium involves both direct effects of E2 on the epithelium (20, 23) and indirect effects mediated through stromal ER (20). E2 effects on uterine PR expression also involve both direct and indirect effects (21), with E2 directly regulating stromal PR expression in uterine stroma, but down-regulating epithelial PR through stromal ER (21). The ability of E2 to modulate LF and PR expression in KO uteri indicates that IGF-I is not required for either direct or indirect E2 effects on LF or PR. Therefore, IGF-I is essential for uterine growth and cell proliferation, but other E2 responses, such as epithelial hypertrophy (increase in height), LF expression, and changes in PR expression, do not require IGF-I.
Hepatic IGF-I mRNA does not change during the estrous cycle in the rat (24), and systemic serum IGF-I levels in ovariectomized rats are not increased by E2 (25). Although E2 does not stimulate systemic IGF-I, it may affect IGF-I signaling through other mechanisms, such as effects on IGFBP-1 though -6, which regulate IGF bioavailability. For example, E2 decreases uterine IGFBP-3 mRNA in ovariectomized rats (26), and IGFBP-4 expression in mouse uterus is regulated throughout the estrous cycle independently of uterine IGF-I expression (15). In ovariectomized IGFBP-1 transgenic mice, which overexpress rat IGFBP-1, uterine weight after estrogen treatment was reduced compared with that in WT mice (4). Thus, E2 could alter liver IGFBP expression and have effects on IGF-I availability and activity, allowing E2 to affect IGF-I signaling without effects on circulating IGF-I levels.
In addition to modulating IGF-I effects through changes in IGFBPs, E2 can have direct effects on IGF-I signaling. E2 enhances tyrosine phosphorylation of IGF-I receptor and insulin receptor substrate-1, which associates with the IGF-I receptor through phosphotyrosine binding domains (27), and E2 also stimulates the binding of insulin receptor substrate-1 and phosphoinositol 3-kinase to the IGF-I receptor in uterus (28). ER is necessary for IGF-I receptor activation by E2 (29), and E2 is able to activate the IGF-I receptor signaling complex only in the presence of IGF-I, as this E2 effect does not occur in the uterus of IGF-I KO mice (28). E2 also stimulates the expression of IGF-I receptor mRNA and protein in uterus (8, 9). Thus, E2 can regulate both IGF-I receptor activation and IGF-I receptor levels, indicating that E2 may modulate IGF-I signaling through mechanisms not involving changes in IGF-I levels.
Systemic IGF-I can support uterine development in the absence of local IGF-I. To determine whether the converse was true, if local IGF-I production alone could support uterine development without systemic IGF-I, we examined the growth of neonatal WT uteri in WT and KO hosts. The WT and KO mice used here were derived from a mixed genetic background, but had been inbred for several generations so WT uteri could be grown in KO hosts or vice versa for extended periods without obvious signs of graft rejection.
The growth of neonatal WT uteri in WT hosts was similar to that in athymic hosts. Conversely, grafted neonatal WT uteri showed minimal growth in KO hosts, indicating that the KO environment is insufficient to support growth of WT uterine grafts. These results must be interpreted with caution, because serum E2 levels are decreased 50% in KO compared with WT mice (2). However, previous literature has indicated that injection of 4 ng/d of E2 into ovariectomized mice, a dose 10% of that necessary to produce maximal uterine growth, still resulted in a 2-fold increase in uterine weight compared with controls after 4 d of treatment (18). This suggests that half-normal E2 levels in the KO mice would most likely be sufficient to support significant, even if reduced, uterine growth. The absence of growth by WT uteri in KO hosts 1 month after grafting suggests that these uteri cannot grow without systemic IGF-I, although the complicating factor of reduced E2 in KO hosts precludes a definitive conclusion on this point. A planned experiment to directly address this point by grafting WT uteri into KO hosts and then injecting exogenous E2 during the 4-wk growth period did not prove feasible due to the reduced vigor of the KO mice and their consequent high mortality after kidney capsule grafting.
The original somatomedin hypothesis of Salmon and Daughaday (30) proposed that GH stimulated liver IGF-I, which then circulated systemically and stimulated the growth of bone and other organs. The subsequent discovery of local IGF-I production in many tissues (31) suggested that IGF-I could cause paracrine/autocrine effects, generating debate about the relative importance of systemic and local IGF-I in growth. Recent descriptions of model systems involving severely reduced systemic IGF-I but near-normal growth (5, 6) led to speculation that local IGF-I is the critical mediator of growth (7). This contrasts with older literature showing that IGF-I injections of hypophysectomized animals can restore most aspects of growth, suggesting that circulating IGF-I can support near-normal growth in the absence of local IGF-I production (32). The present results showing normal growth and E2 responsiveness of KO uteri in an environment containing only systemic IGF-I indicate that recent emphasis on local IGF-I as the most important or even sole mediator of growth induced by IGF-I may be an oversimplification, at least for the uterus. Whether this idea is applicable to other organs remains to be determined. Clearly, although local IGF-I production may be sufficient to induce normal uterine growth, in the grafted uterus it is not necessary, suggesting that both systemic and local IGF-I may play critical roles in growth in vivo.
In summary, systemic IGF-I alone can support normal uterine development and epithelial proliferation in response to E2. Therefore, the increase in local uterine IGF-I in response to E2 is not obligatory for normal uterine growth or E2-induced epithelial proliferation. These results indicate that systemic IGF-I is more important for growth of uterus and possibly other tissues than previously thought, although the precise relationship between local and systemic IGF-I in uterine growth and E2 responsiveness remains to be determined. In contrast, neither systemic nor local IGF-I is obligatory for E2-induced changes in the expression of LF and PR, indicating that IGF-I is not necessary for other uterine responses to E2.
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Footnotes |
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1 Present address: Graduate School of Integrated Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236-0027, Japan. 
Abbreviations: BW, Body weight; IGFBP-1, IGF-binding protein-1; KO, knockout; LF, lactoferrin; LI, labeling index; WT, wild-type.
Received October 15, 2001.
Accepted for publication March 6, 2002.
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knockout mouse. Biol Reprod 59:470–475. Endocrinology 141:3430–343 participation in the mouse uterine epithelial secretory response. Endocrinology 140:484–491 rapidly activates the IGF-I receptor pathway. J Biol Chem 275:18447–18453This article has been cited by other articles:
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