Upregulation of Indian Hedgehog Gene in the Uterine Epithelium by Leukemia Inhibitory Factor During Mouse Implantation

Wakitani, Shoichi; Hondo, Eiichi; Phichitraslip, Thanmaporn; Stewart, Colin L.; Kiso, Yasuo

doi:10.1262/jrd.19120

Cited by 24 publications

(29 citation statements)

References 28 publications

(53 reference statements)

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“…A more complicated picture emerged in studies with a rat delayed implantation model in which treatment with estradiol increased Ihh expression (Kubota et al 2010). In addition to stimulation mediated through PGR, expression of Ihh was shown to be increased by injection of LIF (Wakitani et al 2008). Studies to date indicate that expression of Ihh increases in the luminal and glandular epithelium before implantation and that expression is regulated by steroid hormones and perhaps other mediators essential for implantation, such as LIF.…”

Section: Introductionmentioning

confidence: 99%

Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss

Harman¹,

Cowan²,

Ren³

et al. 2011

Reproduction

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The role of the hedgehog (HH) signaling pathway in implantation was studied in mice in which the HH signal transducer, smoothened (SMO), was conditionally deleted in the stromal compartment of the uterus, using CRE recombinase expressed through the Amhr2 -mutant mice, Smo mRNA in uterine stroma was reduced 49% compared to that in Amhr2control mice, while levels in the luminal epithelium were not different. Litter size was reduced 60% in mutants compared with controls, but ovulation rate and the number of implantation sites on day 7 of pregnancy did not differ. The number of corpora lutea was equivalent to the number of implantation sites, indicating that most ovulations resulted in implanted embryos. However, on days 13 to 15, the rate of embryo resorption was elevated in mutants. In control mice, on day 5, implantation sites were present and blastocysts were well-attached. In contrast, blastocysts were readily flushed from uteri of mutant mice on day 5 and implantation sites were rare. On days 5.5 and 6, implantation sites were present in mutant mice, and by day 6 embryos could not be flushed from the uterus. The weight of implantation sites on day 7 was decreased by 42% in mutant mice, consistent with delayed development. Signaling through SMO in the endometrial stroma is required for optimal timing of implantation, and deferred implantation leads to defective embryo development and subsequent pregnancy loss.

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Section: Introductionmentioning

confidence: 99%

Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss

Harman¹,

Cowan²,

Ren³

et al. 2011

Reproduction

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“…In fact, its expression pattern was somewhat similar to LIF, which has been demonstrated to play critical roles for uterine preparation and embryo implantation [18][19][20]. Indeed, there is evidence that Wnt signaling and LIF mediate over- lapping functions in maintenance of the pluripotency of mouse ES cells [21].…”

Section: Discussionmentioning

confidence: 89%

“…Dev. 55: [17][18][19][20][21][22]2009) nt signaling pathways play important roles in various processes such as fetal development, tumorigenesis and homeostasis. When Wnt ligands bind to two receptors, Frizzled (Fz) proteins and lipoprotein receptor-relate proteins 5 and 6 (LRP5/6), classic canonical Wnt signaling is activated.…”

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confidence: 99%

Expression and Regulation of Dickkopf2 During Periimplantation in Mice

Zhang

Peng

Kuang

et al. 2009

Journal of Reproduction and Development

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Abstract. Successful implantation depends on active dialogue between the maternal endometrium and the implanting blastocysts that is well controlled by groups of regulators at the molecular level. Dickkopf2 (Dkk2) is a member of Dickkopf family normally acting as an antagonist of canonical Wnt/beta-catenin signaling, which has been proven to participate in tumorigenesis and early embryo development. In order to explore the potential function of Dkk2 in embryo implantation, the present study investigated the uterine expression and regulation profiles of Dkk2 during periimplantation in mice. Using reverse transcription-polymerase chain reaction, immunohistochemistry and Western blotting, we showed that the mRNA and protein levels of Dkk2 began to increase in the glandular epithelium on day 4, continued to increase on day 5 and then decreased from day 6 of pregnancy. Moreover, on days 5-8 of pregnancy, Dkk2 was increasingly expressed in the deciduum of the uterus, especially around the implanting embryos. In addition, upregulation of Dkk2 was also observed in uteri treated with estrogen (estradiol-17β) as well as in oil-induced artificial decidualization, indicating that the expression of Dkk2 could be induced by both steroid hormone (estrogen) and the process of decidualization. Furthermore, in the postimplantation uterus, the Dkk2 protein showed an inversed expression with active beta-catenin from day 6 onward, supporting the notion that Dkk2 plays an inhibitory role against canonical Wnt signaling in the context of the decidualizing stroma. Collectively, our data suggests that Dkk2 expression is associated with uterine receptivity changes as well as the process of decidualization and that it might play important roles through inhibition of canonical Wnt signaling in the periimplantation uterus.

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“…Ovariectomized mice treated with both P4 and E2 show no expression of Ihh gene [6]. Wakitani et al [28] reported that leukemia inhibitory factor (Lif) can induce Ihh expression during the implantation period. As Lif is induced by E2, the tissue remodeling of the uterus mediated by Ihh must include the involvement of not only P4 but also E2.…”

Section: Discussionmentioning

confidence: 99%

Expression of Hedgehog Family Genes in the Rat Uterus During Early Pregnancy

Kubota

Yamauchi

Matsumoto

et al. 2008

Journal of Reproduction and Development

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Abstract. Hedgehog (Hh) plays a pivotal role in various tissues during embryonic development, tissue homeostasis and tumorigenesis. In mammals, Hh exists in three homologs: Desert hedgehog (Dhh), Indian hedgehog (Ihh) and Sonic hedgehog (Shh). In this study, we cloned full-length cDNAs encoding Dhh and Ihh from the rat uterus. Their amino acid sequences have a high homology with those of the mouse and human. In addition, the changes of Hh gene expression in the rat uterus during early pregnancy were analyzed. The results showed that all three hedgehog mRNAs were detected in the rat uterus at the proestrus stage and during early pregnancy (1.5, 3.5, 5.5 and 7.5 days post coitus: dpc). Ihh mRNA expression varied and peaked at 3.5 dpc in the luminal and glandular epithelium. Expression was decreased on 5.5 dpc with the exception of sustained expression in the glandular epithelium. Despite such Ihh variability, the expressions of Dhh and Shh mRNA remained unchanged. This indicated that Ihh was mainly expressed in the rat uterus during early pregnancy. Moreover, the Hh target gene (glioma-associated oncogene homolog 1; Gli1) was also highly expressed at 3.5 dpc in the epithelium and periepithelial stroma in a manner similar to the temporal pattern of Ihh expression. This suggests that Ihh signaling axis play a role in the rat uterus during early pregnancy. In summary, our results elucidate that Ihh is a predominant Hh protein in the rat uterus during early pregnancy and that other Hhs have the potential to be expressed. This observation will help to elucidate the basic molecular mechanism of rat uterus during early pregnancy. Key words: Hedgehog, Implantation, Rat, Uterus (J. Reprod. Dev. 54: [340][341][342][343][344][345] 2008) regnancy in mammals is accompanied by dramatic remodeling of uterine tissue, which provides optimal conditions for subsequent embryo implantation and development. In early pregnancy, the mammal's endometrial epithelial and stromal cells undergo rapid and coordinated proliferation and differentiation in response to steroid hormones, 17β-estradiol (E2) and progesterone (P4) [1,2]. In rodents, E2 stimulates epithelial cells to initiate proliferation on days 1 to 3 of pregnancy. Then P4, in combination with continuation of E2 stimuli, triggers epithelial cell differentiation and stromal cell proliferation. By day 4 or 5, the epithelial and stromal cells are tidily differentiated in final preparation for embryo attachment and implantation [3]. As a result, the endometrium acquires uterine receptivity, allowing for various reactions such as implantation and decidualization. However, in spite of all we know regarding the many aspects of the receptive uterus, the frequency of occurrence of female infertility begs a deeper understanding, particularly, of the details of hormonal control of the molecular and cellular mechanisms involved. These things remain unclear, in part, due to the nature of the intricate signaling hierarchy process and complex dynamics of subsequent morphological change. In addi...

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Upregulation of Indian Hedgehog Gene in the Uterine Epithelium by Leukemia Inhibitory Factor During Mouse Implantation

Cited by 24 publications

References 28 publications

Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss

Reduced signaling through the hedgehog pathway in the uterine stroma causes deferred implantation and embryonic loss

Expression and Regulation of Dickkopf2 During Periimplantation in Mice

Expression of Hedgehog Family Genes in the Rat Uterus During Early Pregnancy

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