Biol Reprod Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow My Folders
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gadd, T.S.
Right arrow Articles by Wathes, D.C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gadd, T.S.
Right arrow Articles by Wathes, D.C.
Agricola
Right arrow Articles by Gadd, T.S.
Right arrow Articles by Wathes, D.C.
Biology of Reproduction 62, 1415-1421 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Article

Regulation and Localization of Insulin-Like Growth Factor Binding Protein-5 Gene Expression in the Uterus and Placenta of the Cyclic and Early Pregnant Ewe1

T.S. Gadd2,a, J.C. Osgerbya, and D.C. Wathesa

a Department of Veterinary Basic Sciences, Royal Veterinary College, Potters Bar, Hertfordshire, EN6 1NB, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The insulin-like growth factor (IGF) system plays an important role in the regulation of uterine function and placental growth. However, there is little information regarding the localization and regulation of IGF binding protein-5 (IGFBP-5) in the reproductive tract. The distribution of this IGFBP was therefore investigated using in situ hybridization in sections of utero-placental tissue obtained throughout the estrous cycle, up to Day 55 of gestation, and on Days 16–17 from both horns of ewes with unilateral pregnancies that followed uterine transection. In nonpregnant ewes, IGFBP-5 mRNA was present at high concentrations in the maternal caruncles and luminal epithelium, and at moderate levels in myometrium. In these regions IGFBP-5 mRNA showed cyclic variations, with concentrations peaking around ovulation, whereas low expression in the endometrial stroma remained constant. During pregnancy, there was additional localization to the endometrial glands; and in all regions, with the exception of the caruncles, concentrations increased significantly with gestational age. In transected uteri, concentrations in the luminal epithelium of the pregnant horn were significantly higher than those in the nonpregnant horn. In the caruncles, IGFBP-5 mRNA formed an intense band just below the tips of the invading fetal villi. Below this band, IGFBP-5 mRNA localized to form a series of rings, which could create a route to allow the fetal villi access into the caruncular stroma for nutrient exchange. In conclusion, IGFBP-5 is abundantly expressed in the ovine reproductive tract, with both the concentration and localization differentially regulated during the cycle and pregnancy.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Evidence suggests that insulin-like growth factor (IGF)-I and -II have important roles to play in the regulation of uterine function as well as placental growth and development [1–3]. The bioavailability of the IGFs are regulated by a family of six binding proteins designated IGFBP-1 through to IGFBP-6. IGFBP-5 is a 29-kDa protein that can both inhibit and potentiate IGF-mediated actions [4, 5]. Inhibition is thought to result from the formation of IGF-IGFBP-5 complexes that prevent IGF from binding to the IGF receptors [6]. Potentiation is thought to involve IGFBP-5 incorporation into the extracellular matrix (ECM) via heparin-binding "consensus" sequences found at the carboxyl-terminal domain. This cell surface-associated IGFBP-5 has lower affinity for the IGFs and possibly provides a mechanism by which IGF may be slowly released from the IGF-IGFBP-5 complex onto the IGF receptors without causing their down-regulation [7].

Furthermore, several IGFBP-5 specific proteases have been isolated [8, 9]. These proteases, thought to be matrix metalloproteinases, cleave the IGF-IGFBP-5 complex, lowering IGFBP's affinity for the IGF, resulting in the dissociation of the IGF from the complex. Interestingly, a 23-kDa proteolytically cleaved fragment of IGFBP-5 has been shown to stimulate mitogenesis in an IGF-independent manner [10]. Although there have been studies investigating the local production of IGFBP-5 in the reproductive tract of a number of different species (cow [11], rodent [12–14], nonhuman primate [15], human [16–18]), the ewe has, to our knowledge, been largely ignored. Therefore, in an attempt to further our understanding of the function and regulation of IGFBP-5 in the reproductive tract, we have mapped its spatial and temporal expression throughout the estrous cycle and during early gestation in the ovine uterus and placenta.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Tissue Samples

Reproductive tracts were taken from 46 nonpregnant ewes throughout the estrous cycle and from 33 pregnant ewes ranging in gestational age from 13 to 55 days. In nonpregnant ewes, the stage of the estrous cycle was regulated by an i.m. injection with Estrumate (Coopers Animal Health Ltd., Crewe, UK), a prostaglandin (PG) analogue given in the midluteal phase to induce estrus. After treatment, estrus can be expected at 48 h, with ovulation occurring at approximately 65 h. The number of samples collected at each time point were as follows: nonpregnant—24 h post-PG (pPG), n = 3; 36 h pPG, n = 6; 48 h pPG, n = 6; 60 h pPG, n = 5; 65 h pPG, n = 3; Days 2–3, n = 6; Day 5, n = 3; Days 7–9, n = 5; Day 13, n = 6; Day 15, n = 3; pregnant—Days 13–22, n = 9; Days 25–30, n = 8; Days 31–41, n = 9; Days 45–55, n = 7. Uterine samples were also collected on Days 16 and 17 from 4 ewes with unilateral pregnancies that followed uterine transection before mating. The horn ipsilateral to an active corpus luteum was sectioned, the endometrium cauterized, and the myometrium of the two ends sutured [19]. Because both horns (the pregnant and nonpregnant) are subject to the same endocrine environment, but are surgically isolated from each other, the technique provides an opportunity to study the effect of local regulatory factors produced by the embryo on IGFBP-5 expression. All animals were kept and treated under the Home Office Animals (Scientific Procedures) Act 1986.

Uteri were dissected transversely into segments of approximately 2–3 cm in length, wrapped in aluminum foil, and frozen in liquid nitrogen-tempered isopentane. Samples were stored at -80°C until sectioning.

Oligonucleotide Probe

The 45-mer oligonucleotide antisense probe corresponded to nucleotides 291–335 of the bovine IGFBP-5 gene [20] and had the following sequence; 5'-TCG-GAG-ATG-CGG-GTG-TGC-TTG-GGC-CGG-AAG-ATC-TTG-GGC-GAG-TAG-3'. A sense probe identical in sequence to the respective mRNA target was included as a negative control. To date, the ovine sequence has not been determined, so the region selected was chosen for 1) its highly homology with other species (pig 97%, human 95%, mouse 91%, rat 88%) and 2) its low homology with other IGFBPs.

In Situ Hybridization

The in situ hybridization procedure was performed as described previously [2]. All chemicals were purchased from Sigma Chemical Co. (Poole, Dorset, UK) or BDH (Poole, Dorset, UK) unless otherwise stated. Briefly, 10-µm cryostat sections were thaw-mounted onto poly-L-lysine-coated slides, fixed in 4% (w:v) paraformaldehyde in 0.01 M PBS, washed in 0.01 M PBS, and dehydrated sequentially in 70% and 95% ethanol. The oligonucleotide probe for IGFBP-5 was [35S]-labeled at the 3'-end using terminal deoxynucleotidyl transferase (Pharmacia Biotechnology, St Albans, Herts, UK). Sections were subsequently hybridized with a 110 000-cpm probe in 200 µl hybridization buffer and incubated overnight at 42°C. After incubation, slides were washed in single-strength SSC (0.15 M sodium chloride, 0.015 M sodium citrate), 0.2% (w:v) sodium thiosulfate pentahydrate solution for 30 min at room temperature, then at higher stringency in single-strength SSC, 0.2% (w:v) sodium thiosulfate pentahydrate solution for 60 min at 55°C. Finally the slides were dehydrated in a gradient of ethanol, air-dried, and exposed to x-ray film (Hyperfilm-ßmax, Amersham International, Aylesbury, UK), for 21 days. Samples of uterus previously shown to be positive for the IGFBP-5 probe [21] were included as a positive control. All samples were processed together in one batch.

Photographic Emulsions

Slides previously exposed to x-ray film were coated with a photographic emulsion, LM1 (Amersham International), according to the manufacturer's instructions, and stored at 4°C for 28 days. Slides were then developed and counterstained with hematoxylin and eosin in order to confirm microscopically the cellular localization of the radioactive signal.

Optical Density (OD) Quantification

The quantification method was performed as described previously [2]. An image analysis system (Seescan PLC, Cambridge, UK) was used to convert the radioactive signals to OD units for quantification using a linear gray scale of 0–2.1. All readings were on this part of the scale. The antisense autoradiograph was placed under the image analyzer lens, and a blank section of the film was measured. The region to be quantified was outlined, and the background reading was automatically subtracted from this. The corresponding section on the sense autoradiograph was measured in a similar fashion, and the reading obtained was subtracted from the antisense value to give the final OD value for the specific hybridization. A minimum of two antisense slides, each containing at least two sections, were measured for each animal, and the average OD value was calculated. The detection limit was taken as an OD > 0.01. The coefficient of variation for duplicate absorbance measurements between two slides was 5%.

Statistical Analysis

Values are given as mean OD ± SEM. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL), version 6.1. Differences between time points were analyzed by unbalanced one-way ANOVA or by an ANOVA of regression. Fisher's tests were used to determine which time points differed. If the data did not exhibit homogeneity of variance, then the Kruskal-Wallis nonparametric one-way ANOVA was used instead. If no time-related changes were detected, all data from a particular region were pooled between time intervals. Results were considered statistically significant when P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
In the nonpregnant uterus, IGFBP-5 mRNA was present at high concentrations in the maternal caruncles and luminal epithelium, at moderate levels in the inner circular muscle layer of the myometrium, and at low levels in the outer longitudinal layer of myometrium (Fig. 1A). In all these regions, IGFBP-5 expression varied significantly throughout the cycle, with concentrations high around the time of ovulation (65 h post-PG), and low in the late luteal phase (Fig. 2, A–D). In the endometrial stroma, IGFBP-5 concentrations remained low and stable (OD 0.03 ± 0.003, n = 44).



View larger version (118K):
[in this window]
[in a new window]
  		FIG. 1. Autoradiographs showing the localization of IGFBP-5 mRNA in ovine uterus. A, C, E, G) Hybridized with antisense probe. B, D, F, H) Hybridized with sense (negative control) probe. A) Cross section of uterine horn taken from a ewe at estrus (48 h post-PG) showing expression in the maternal caruncles (C), luminal epithelium (LE), inner and outer myometrium (IM and OM, respectively), and stroma (S). C) Section from a Day 20 pregnant ewe showing a decreasing gradient of expression from the fetal to the maternal side of the caruncle. E) Section from a Day 30 pregnant ewe showing additional expression in the endometrial glands (G). F) Section of placentome taken from a Day 40 pregnant ewe showing expression in the placentome capsule (PC). Note the high level of nonspecific binding in G and H. The scale bar represents 1 mm in each case



View larger version (22K):
[in this window]
[in a new window]
  		FIG. 2. IGFBP-5 mRNA concentrations in the nonpregnant uterus throughout the estrous cycle measured as OD units from autoradiographs. Follicular phase samples were collected at timed intervals after PG-induced luteolysis (pPG). Note the difference in scale between the graphs. Between 2 and 6 animals were analyzed at each time point. A) Expression in the luminal epithelium (a–d, P < 0.0001). B) Expression in the inner myometrium (P < 0.009). C) Expression in the outer myometrium (P < 0.02). D) Expression in the caruncular stroma (P < 0.0006)

During pregnancy, IGFBP-5 was produced in the same regions with additional localization to the endometrial glands (Figs. 1E and 3A). Highest levels of IGFBP-5 mRNA expression were found in the luminal epithelium and endometrial glands (Fig. 1E and Fig. 3, A–C). In these regions, levels of expression were initially modest, but showed a significant increase as gestation progressed (Fig. 4, A and B, P < 0.01). In the inner circular layer of myometrium, concentrations of IGFBP-5 also increased with time (P < 0.05), with concentrations initially low and rising to moderate levels at Day 55 (Fig. 4C). Concentrations in the outer myometrium and endometrial stroma were below the limit of detection, OD < 0.01.



View larger version (142K):
[in this window]
[in a new window]
  		FIG. 3. Photographic emulsions showing the cellular localization of IGFBP-5 in the pregnant uterus. A, C, D, E) Hybridized with antisense probe. B, F) Hybridized with sense (control) probe. A) Intense expression of IGFBP-5 in the endometrial glands (G) of a Day 40 pregnant ewe. C) Intense expression in the luminal epithelium (LE) also taken from a ewe at Day 40 of gestation. Note there is no localization to the fetal trophoblast (FT) or fetal mesoderm (FM). D) Section through a placentome at Day 32 showing the intense band of IGFBP-5 mRNA located just below the boundary of the invading fetal villi (F, fetal; M, maternal). Note below this band how IGFBP-5 localizes into a series of ring shapes (R). E) High-power version of D showing one of the rings of IGFBP-5 mRNA. F) Sense control section of placentome showing that the ring structure is not IGFBP-5 hybridizing to blood vessels but rather caruncular stroma that has seemingly begun to circularize. The scale bar represents 200 µm in A–C, 500 µm in D, and 50 µm in E and F.



View larger version (17K):
[in this window]
[in a new window]
  		FIG. 4. IGFBP-5 mRNA concentration in the ovine uterus throughout gestation measured as OD units from autoradiographs. Note the difference in scale between graphs. Between 7 and 9 animals were analyzed at each time point. A) Expression in the luminal epithelium. B) Expression in the endometrial glands. C) Expression in the inner myometrium. In all cases there was a significant increase in concentration over time (A and B, P < 0.01; C, P < 0.05).

In the caruncles, there was an intense band of IGFBP-5 mRNA localized just below the tips of invading fetal villi (Figs. 1C and 3D). As the villi penetrated deeper into the caruncle, this band was observed to retreat, such that by Day 40 it occupied only the region of the placentome capsule (Fig. 1G). Photographic emulsions revealed that below this band, the IGFBP-5 mRNA hybridized to form a series of circles (Fig. 3, D and E, Fig. 5). Careful analysis confirmed that this was not IGFBP-5 mRNA hybridizing to blood vessel walls as was expected. Instead, the IGFBP-5 appeared to hybridize to specific areas of caruncular stroma, which had seemingly become organized into circular structures (Fig. 3F). The identity of these circular structures and their significance remains to be determined. There was no hybridization to any fetal tissue.



View larger version (11K):
[in this window]
[in a new window]
  		FIG. 5. Lower-power schematic diagram of Figure 3D showing the exact localization pattern for IGFBP-5 mRNA in the ovine placentome. The IGFBP-5 was expressed as an intense band followed by a series of ring shapes just below the tips of the invading fetal villi. The different regions shown are F, fetal; M, maternal; FV, fetal villi; CS, caruncular stroma.

In the transected uteri on Days 16–17 of gestation, concentrations in the luminal epithelium of the pregnant horn were significantly higher than levels in the nonpregnant horn (Fig. 6, P < 0.01). In all other regions there was no significant difference in IGFBP-5 concentration between horns.



View larger version (11K):
[in this window]
[in a new window]
  		FIG. 6. Concentrations of IGFBP-5 mRNA in the luminal epithelium of pregnant and nonpregnant horns from transected uteri on Days 16–17 of gestation (a,b, P < 0.01, n = 4)


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study represents the first attempt to provide detailed maps of the expression pattern for IGFBP-5 in the ovine reproductive tract throughout the estrous cycle and for the first trimester of gestation. The study has clearly shown that IGFBP-5 exhibits cell-specific expression that is strongly influenced by the stage of the estrous cycle as well as the stage of gestation.

During the estrous cycle, IGFBP-5 concentrations were highest in the luminal epithelium and caruncular stroma, with moderate expression in the inner myometrium and low expression in the endometrial stroma. Similar findings have been shown in the rat, with IGFBP-5 protein localized to the luminal epithelium and outer myometrium [18] and IGFBP-5 mRNA localized to both muscle layers of the myometrium [13]. In the cow, IGFBP-5 has been found in the caruncles, endometrial stroma, and myometrium [11], with stronger expression recorded in the inner than the outer muscle layers of the myometrium (unpublished observations). In all regions, with the exception of the endometrial stroma, IGFBP-5 showed cyclic variations in expression, with levels particularly high around the time of ovulation. Concentrations declined significantly in the luteal phase, suggestive perhaps of regulation by ovarian steroid hormones. In human endometrium, IGFBP-5 is more dominant in the follicular phase [16], and in ovariectomized nonhuman primates, estradiol positively regulates IGFBP-5 expression in the myometrium [15]. By comparison, in the rat, IGFBP-5 expression predominates in the luteal phase [13], with estradiol negatively regulating IGFBP-5 in uteri of ovariectomized rats [18]. Collectively, these discrepancies must represent a species-specific difference in the steroidal regulation of IGFBP-5, with the sheep more closely resembling the regulatory system of the nonhuman primate than that of the rat. In the 5' flanking region of the rat IGFBP-5 gene, there are multiple cis-regulatory elements, including progesterone and estrogen-receptor binding sites [22]. Whether such elements exist in the ovine promoter region remains to be determined. IGFBP-5 can both potentiate and inhibit the mitogenic actions of the IGFs. We speculate that its abundant, almost ubiquitous, expression in the cyclic uterus suggests that it is an important physiological modulator of IGF-I and IGF-II. We and others have previously reported that mRNAs for both these peptides and the type 1 IGF receptor are present in the ovine uterus during the cycle, with a significant up-regulation of endometrial IGF-I mRNA expression at estrus [23–25].

Studies from our laboratory have also shown that IGFBP-5 is the most abundantly expressed of the IGF binding proteins in the pregnant ovine uterus (unpublished observations). Its expression appeared to be developmentally regulated, increasing in the luminal epithelium, endometrial glands, and myometrium as gestation progressed. In the rat, IGFBP-5 expression increases in the myometrium during pregnancy, peaks mid-gestation, and thereafter becomes limited [12]. In primates, local IGF-I mRNA levels were significantly correlated with local myometrial cell proliferation [15], and high levels of IGFBP-5 have been observed in developing embryonic muscles [26, 27]. These data taken together with the current data would support a role for IGFBP-5 in modulating uterine muscle growth.

There was also intense and increasing expression of IGFBP-5 in the endometrial glands and luminal epithelium during pregnancy. In the glands, IGFBP-5 in conjunction with the type 1 receptor could modulate glandular secretions contributing to the uterine milieu. The fact that IGFBP-5 is colocalized with four other IGF binding proteins (IGFBP-2, -3, -4, and -6) and IGF-2R at the fetal-maternal interface at this time [2, 25] implies the importance of tight regulation of IGF activity occurring in and around this region. It is possible that this multitude of IGFBPs functions to create a large reservoir of IGFs, which could then be targeted to certain tissues, fetal or maternal.

Interestingly, the up-regulation of uterine IGFBP-5 is coincidental with the down-regulation of uterine IGFBP-3 [2], a finding that is reciprocated in the nonhuman primate myometrium [15] and in human intestinal muscle [28]. However, why IGFBP-3 and IGFBP-5 should be regulated in reciprocal fashion in these tissues remains to be determined.

The most intriguing finding was the pattern of IGFBP-5 expression in the caruncles, the sites of trophoblast invasion. In this region, the IGFBP-5 formed a band followed by a series of rings just below the tips of the invading fetal villi. Recent evidence has implicated IGFBP-5 in the induction of apoptosis as it is up-regulated in atretic ovarian follicles [29], involuting thyroid, prostate, and mammary glands [30, 31], as well as in fetal interdigital webs just before their deletion (D.J. Flint, Hannah Research Institute, Ayr, UK, personal communication). In view of this, one could speculate that the IGFBP-5 localized in this region functions to create a route or a series of channels to allow the fetal villi access into the caruncular stroma. The formation of a network of such channels has been reported in ruminant caruncles just before villus penetration [32]. We are currently investigating this phenomenon.

In the transected uteri, IGFBP-5 was up-regulated in the luminal epithelium of the pregnant horn. This finding is in agreement with Keller et al. [11], who found that binding of [125I]-IGF-I by proteins in the 29- to 31-kDa range was greater in pregnant than nonpregnant cow endometrium on Days 13 and 15. Since both horns in our studies were subject to the same endocrine environment, the results suggest that an embryonic factor, acting via a paracrine mechanism, functions to up-regulate IGFBP-5 at the level of transcription. One possible candidate for this is IGF-II, which in rat osteoblast and chondrocyte cultures causes dose-dependent increases in the level of both IGFBP-5 mRNA and peptide [33, 34]. In sheep, IGF-II is secreted from the adjacent fetal mesoderm in significantly increasing amounts towards term [2]. The antiluteolytic hormone, ovine interferon-tau, is unlikely to up-regulate IGFBP-5 transcription since it is down-regulated by Day 21, when IGFBP-5 levels are still continuing to rise [35].

IGFBP-5 is abundantly expressed in rodent and human placenta and fetal membranes [14, 17], as well as in bovine blastocysts [36]. In this study, however, there was no evidence for hybridization of IGFBP-5 to any fetal tissue. Its presence in the preimplantation ovine blastocyst cannot, however, be excluded, as no attempt was made to preserve or include blastocysts in the tissue collected for the purposes of this study.

In summary, our data have shown that IGFBP-5 mRNA is abundantly expressed in ovine uterus. IGFBP-5 shows cyclic variations in expression, with levels peaking around ovulation, perhaps suggestive of regulation by estradiol. During pregnancy, IGFBP-5 appears to be developmentally regulated, with levels increasing with gestational age. Increased concentrations of IGFBP-5 in the pregnant horn of transected uteri indicate that an embryonic factor functions to stimulate IGFBP-5 via a paracrine mechanism. Unique rings of IGFBP-5 mRNA localized in the caruncles suggest that this binding protein may be involved in creating a route to allow the fetal villi access into the caruncular stroma. This hypothesis is supported by recent evidence for a role for IGFBP-5 in apoptosis. Intense glandular and luminal epithelial expression could enable IGFBP-5 to facilitate the transfer of IGFs across the maternal-fetal interface, while localization to the myometrium could suggest a role for IGFBP-5 in modulating uterine muscle growth.


   ACKNOWLEDGMENTS
 
We would like to thank Mr. J. Thompson for the care of the animals; Professor G.E. Lamming and Professor A.P.F. Flint from the University of Nottingham for kindly providing the transected uteri; and Mrs. B. Wilsmore for her assistance with the photography.


   FOOTNOTES
 
First decision: 10 September 1999.

1 Financial support provided by the Wellcome Trust; J.C.O. was supported by a studentship from the Biotechnology and Biological Sciences Research Council. Back

2 Correspondence: T.S. Gadd, Department of Veterinary Basic Sciences, The Royal Veterinary College, Boltons Park, Hawkshead Road, Potters Bar, Herts, EN6 1NB, United Kingdom. FAX: 01707 647085; treynold{at}rvc.ac.uk Back

Accepted: December 31, 1999.

Received: July 27, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Giudice LC, Irwin JC, Dsupin BA, Des Las Fuentes, Jin IH, Vu TH, Hoffman AR. Insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and IGFBP protease in human uterine endometrium: their potential relevance to endometrial cyclic function and maternal-embryonic interactions. In: Baxter RC, Gluckman PD, Rosenfeld RG (eds.), The Insulin-Like Growth Factors and Their Regulatory Proteins. Amsterdam: Excerpta Med Int Congr Ser. 1056; 1994: 351–361.
  2. Reynolds TS, Stevenson KR, Wathes DC. Pregnancy-specific alterations in the expression of the insulin-like growth factor system during early placental development in the ewe. Endocrinology 1997; 138:886–897.[Abstract/Free Full Text]
  3. DeChiara TM, Efstratiadis A, Robertson EJ. A growth deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting. Nature 1990; 345:78–80.[CrossRef][Medline]
  4. Conover CA, Keifer MC. Regulation and biological effect of endogenous insulin-like growth factor binding protein-5 in human osteoblastic cells. J Clin Endocrinol Metab 1993; 76:1153–1159.[Abstract]
  5. Jones JI, Gockerman A, Busby WH, Camacho-Hubner C, Clemmons DR. Extracellular matrix contains insulin-like growth factor binding protein-5: potentiation of the effects of IGF-I. J Cell Biol 1993; 121:679–687.[Abstract/Free Full Text]
  6. DeMellow JSM, Baxter RC. Growth hormone dependent insulin-like growth factor (IGF) binding protein both inhibits and potentiates IGF-I stimulated DNA synthesis in human skin fibroblasts. Biochem Biophys Res Commun 1988; 156:199–204.[CrossRef][Medline]
  7. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16:3–34.[Abstract/Free Full Text]
  8. Thrailkill KM, Quarles LD, Nagase H, Suzuki K, Serra DM, Fowlkes JL. Characterization of insulin-like growth factor binding protein-5-degrading proteases produced throughout murine osteoblast differentiation. Endocrinology 1995; 136:3527–3533.[Abstract]
  9. Nam TJ, Busby WH, Clemmons DR. Characterization and determination of the relative abundance of two types of insulin-like growth factor binding protein-5 proteases that are secreted by human fibroblasts. Endocrinology 1996; 137:5530–5536.[Abstract]
  10. Andress DL, Birnbaum RS. Human osteoblast derived insulin-like growth factor (IGF) binding protein-5 stimulates osteoblast mitogenesis and potentiates IGF action. J Biol Chem 1992; 267:22467–22472.[Abstract/Free Full Text]
  11. Keller ML, Roberts AJ, Seidel GE. Characterization of insulin-like growth factor-binding proteins in the uterus and conceptus during early conceptus elongation in cattle. Biol Reprod 1998; 59:632–642.[Abstract/Free Full Text]
  12. Cerro JA, Pintar JE. Insulin-like growth factor-binding protein gene expression in the pregnant rat uterus and placenta. Dev Biol 1997; 184:278–295.[CrossRef][Medline]
  13. Girvigian MR, Nakatani A, Ling N, Shimasaki S, Erickson GF. Insulin-like growth factor-binding proteins show distinct patterns of expression in the rat uterus. Biol Reprod 1994; 51:296–302.[Abstract]
  14. Kleffens M, Groffen C, Lindenbergh-Kortleve DJ, Neck JW, Gonzalez-Parra S, Dits N, Zwarthoff EC, Drop SLS. The IGF system during fetal-placental development of the mouse. Mol Cell Endocrinol 1998; 140:129–135.[CrossRef][Medline]
  15. Adesanya OO, Zhou J, Bondy CA. Cellular localization and sex steroid regulation of insulin-like growth factor-binding protein messenger ribonucleic acids in the primate myometrium. J Clin Endocrinol Metab 1996; 81:2495–2501.[Abstract]
  16. Zhou J, Dsupin BA, Giudice LC, Bondy CA. Insulin-like growth factor system gene expression in human endometrium during the menstrual cycle. J Clin Endocrinol Metab 1994; 79:1723–1734.[Abstract]
  17. Han VKM, Bassett N, Walton J, Challis JRG. The expression of insulin-like growth factor (IGF) and IGF binding protein (IGFBP) genes in human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab 1996; 81:2680–2693.[Abstract]
  18. Huynh H. Suppression of uterine insulin-like growth factor-binding protein 5 by estrogen is mediated in part by insulin-like growth factor-I. Int J Oncol 1998; 12:427–432.[Medline]
  19. Lamming GE, Wathes DC, Flint APF, Payne JH, Stevenson KR, Vallet JL. Local action of trophoblast interferons in suppression of the development of oxytocin and oestradiol receptors in ovine endometrium. J Reprod Fertil 1995; 105:165–175.[Abstract/Free Full Text]
  20. Moser DR, Lowe WL, Dake BL, Booth BA, Boes M, Clemmons DR, Bar RS. Endothelial cells express insulin-like growth factor binding proteins 2 to 6. Mol Endocrinol 1992; 6:1805–1814.[Abstract/Free Full Text]
  21. Reynolds TS, Wathes DC, Aitken RP, Wallace JM. Expression of insulin-like growth factor-5 (IGFBP-5) in the pregnant ovine uterus. J Reprod Fertil Abstr Ser 1997; 19:124.
  22. Zhu X, Ling N, Shimasaki S. Cloning of the rat insulin-like growth factor binding protein-5 gene and DNA sequence analysis of its promoter region. Biochem Biophys Res Commun 1993; 15:1045–1052.
  23. Stevenson KR, Gilmour RS, Wathes DC. Localization of insulin-like growth factor-I (IGF-I) and -II messenger ribonucleic acid and type 1 IGF receptors in the ovine uterus during the estrous cycle and early pregnancy. Endocrinology 1994; 134:1655–1664.[Abstract/Free Full Text]
  24. Cann CH, Fairclough RJ, Sutton R, Gow CB. Endometrial expression of mRNA encoding insulin-like growth factors I and II and IGF-binding proteins 1 and 2 in early pregnant ewes. J Reprod Fertil 1997; 111:7–11.[Abstract/Free Full Text]
  25. Wathes DC, Reynolds TS, Robinson RS, Stevenson KR. Role of the insulin-like growth factor system in uterine function and placental development in ruminants. J Dairy Sci 1998; 81:1778–1789.[Abstract]
  26. Schuller AGP, Zwarthoff EC, Drop SLS. Gene expression of six insulin-like growth factor binding proteins in the mouse conceptus during mid- and late gestation. Endocrinology 1993; 132:2544–2550.[Abstract/Free Full Text]
  27. Green BN, Jones SB, Streck RD, Wood TL, Rotwein P, Pintar JE. Distinct expression of insulin-like growth factor binding proteins 2 and 5 during fetal and postnatal development. Endocrinology 1994; 134:954–962.[Abstract/Free Full Text]
  28. Bushman TL, Kuemmerle JF. IGFBP-3 and IGFBP-5 production by human intestinal muscle: reciprocal regulation by endogenous TGF-beta 1. Am J Physiol 1998; 275:1282–1290.
  29. Monget P, Pisselet C, Monniaux D. Expression of insulin-like growth factor binding protein-5 by ovine granulosa cells is regulated by cell density and programmed cell death in vitro. J Cell Physiol 1998; 177:13–25.[CrossRef][Medline]
  30. Guennette RS, Tenniswood M. The role of insulin-like binding proteins (IGFBPs) in regulating active cell death in regressing rat prostate and mammary gland. J Cell Biochem 1995; 19B(suppl):280.
  31. Tonner E, Barber MC, Travers MT, Logan A, Flint DJ. Hormonal control of insulin-like growth factor binding protein-5 production in the involuting mammary gland of the rat. Endocrinology 1997; 138:5101–5107.[Abstract/Free Full Text]
  32. Hradecky P, Mossman HW, Stott GG. Comparative development of ruminant placentomes. Theriogenology 1988; 29:714–729.
  33. McCarthy TL, Casinghino S, Centrella M, Canalis E. Complex pattern of insulin-like growth factor binding protein expression in primary rat osteoblast enriched cultures: regulation by prostaglandin E2, growth hormone, and of insulin-like growth factors. J Cell Physiol 1994; 160:163–175.[CrossRef][Medline]
  34. Matsumoto T, Gargosky SE, Oh Y, Rosenfeld RG. Transcriptional regulation of insulin-like growth factor binding protein-5 in rat articular chondrocytes. J Endocrinol 1996; 148:355–369.[Abstract/Free Full Text]
  35. Roberts RM, Cross JA, Leaman DW. Interferons as hormones of pregnancy. Endocr Rev 1992; 13:432–452.[Abstract/Free Full Text]
  36. Winger QA, Rios P, Han VKM, Armstrong DT, Hill DJ. Bovine oviductal and embryonic insulin-like growth factor-binding proteins: possible regulators of "embryotrophic" insulin-like growth factor circuits. Biol Reprod 1997; 56:1415–1423.[Abstract]



This article has been cited by other articles:


Home page
 Biol. Reprod.Home page
M. C. Satterfield, K. Hayashi, G. Song, S. G. Black, F. W. Bazer, and T. E. Spencer
Progesterone Regulates FGF10, MET, IGFBP1, and IGFBP3 in the Endometrium of the Ovine Uterus
Biol Reprod, December 1, 2008; 79(6): 1226 - 1236.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. Kim, G. Song, H. Gao, J. L. Farmer, M. C. Satterfield, R. C. Burghardt, G. Wu, G. A. Johnson, T. E. Spencer, and F. W. Bazer
Insulin-Like Growth Factor II Activates Phosphatidylinositol 3-Kinase-Protooncogenic Protein Kinase 1 and Mitogen-Activated Protein Kinase Cell Signaling Pathways, and Stimulates Migration of Ovine Trophectoderm Cells
Endocrinology, June 1, 2008; 149(6): 3085 - 3094.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
O. Shynlova, P. Tsui, A. Dorogin, B. L. Langille, and S. J. Lye
Insulin-like Growth Factors and Their Binding Proteins Define Specific Phases of Myometrial Differentiation During Pregnancy in the Rat
Biol Reprod, April 1, 2007; 76(4): 571 - 578.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
C K Hilleson-Gayne and J A Clapper
Effects of decreased estradiol-17{beta} on the serum and anterior pituitary IGF-I system in pigs
J. Endocrinol., December 1, 2005; 187(3): 369 - 378.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
M Munoz-Gutierrez, P A Findlay, C L Adam, G Wax, B K Campbell, N R Kendall, M Khalid, M Forsberg, and R J Scaramuzzi
The ovarian expression of mRNAs for aromatase, IGF-I receptor, IGF-binding protein-2, -4 and -5, leptin and leptin receptor in cycling ewes after three days of leptin infusion
Reproduction, December 1, 2005; 130(6): 869 - 881.
[Abstract] [Full Text] [PDF]

Home page
 ReproductionHome page
K. Hayashi, K. D Carpenter, T. H Welsh Jr, R. C Burghardt, L. J Spicer, and T. E Spencer
The IGF system in the neonatal ovine uterus
Reproduction, March 1, 2005; 129(3): 337 - 347.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow My Folders
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gadd, T.S.
Right arrow Articles by Wathes, D.C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gadd, T.S.
Right arrow Articles by Wathes, D.C.
Agricola
Right arrow Articles by Gadd, T.S.
Right arrow Articles by Wathes, D.C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS