Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus

Lee, Kevin; Jeong, Jaewook; Kwak, Ihn‐Sil; Yu, Cheng-Tai; Lanske, Beate; Soegiarto, Desi W.; Toftgárd, Rune; Tsai, Ming‐Jer; Tsai, Sophia Y.; Lydon, John P.; DeMayo, Francesco J.

doi:10.1038/ng1874

Cited by 252 publications

(309 citation statements)

References 26 publications

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“…However, implantation sites were observed in 6 of 9 WT but only 0 of 6 in UtEpiαERKO after natural mating or embryo transfer into pseudopregnant females, indicating that UtEpiαERKO mice have a compromised uterine embryo receptivity. Accordingly, the estrogen-regulated transcripts Lif (leukemia inhibitory factor) and Ihh (Indian hedgehog), which are essential for embryo attachment (23,24), remained unchanged in UtEpiαERKO but were up-regulated in WT after E 2 treatment (Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

Winuthayanon

Hewitt

Orvis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

204

243

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Female fertility requires estrogen to specifically stimulate estrogen receptor α (ERα)-dependent growth of the uterine epithelium in adult mice, while immature females show proliferation in both stroma and epithelium. To address the relative roles of ERα in mediating estrogen action in uterine epithelium versus stroma, a uterine epithelial-specific ERα knockout (UtEpiαERKO) mouse line was generated by crossing Esr mice with Wnt7a-Cre mice. Expression of Wnt7a directed Cre activity generated selective deletion of ERα in uterine epithelium, and female UtEpiαERKO are infertile. Herein, we demonstrate that 17β-estradiol (E 2 )-induced uterine epithelial proliferation was independent of uterine epithelial ERα because DNA synthesis and up-regulation of mitogenic mediators were sustained in UtEpiαERKO uteri after E 2 treatment. IGF-1 treatment resulted in ligand-independent ER activation in both wildtype (WT) and UtEpiαERKO and mimicked the E 2 stimulatory effect on DNA synthesis in uterine epithelium. Uterine epithelial ERα was necessary to induce lactoferrin, an E 2 -regulated secretory protein selectively synthesized in the uterine epithelium. However, loss of uterine epithelial ERα did not alter the E 2 -dependent progesterone receptor (PR) down-regulation in epithelium. Strikingly, the uterine epithelium of UtEpiαERKO had robust evidence of apoptosis after 3 d of E 2 treatment. Therefore, we surmise that estrogen induced uterine hyperplasia involves a dispensable role for uterine epithelial ERα in the proliferative response, but ERα is required subsequent to proliferation to prevent uterine epithelial apoptosis assuring the full uterine epithelial response, illustrating the differential cellular roles for ERα in uterine tissue and its contribution during pregnancy.conditional knockout | paracrine regulation

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Section: Resultsmentioning

confidence: 99%

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

Winuthayanon

Hewitt

Orvis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

204

243

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“…3 A and B). The expressions of Pgr-regulated genes Indian hedgehog (Ihh) (18), amphiregulin (Areg) (19), homobox A10 (Hoxa10) (20), nuclear receptor subfamily 2, group F, member 2 (Nr2f2) (18), and heart and neural crest derivatives expressed transcript 2 (Hand2) (21) were significantly decreased, and E2 target genes mucin 1 (Muc1), Muc4, lactotransferrin (Ltf), and complement component 3 (C3) (21,22) were significantly increased in OEx mice compared with control mice (Fig. 3 C and D).…”

Section: N1icd Overexpression Mice Are Completely Infertile Because Omentioning

confidence: 99%

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

Strug

Jeong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In mammalian reproduction, implantation is one of the most critical events. Failure of implantation and the subsequent decidualization contribute to more than 75% of pregnancy losses in women. Our laboratory has previously reported that inhibition of Notch signaling results in impaired decidualization in both women and a transgenic mouse model. In this study, we generated a Notch gain-of-function transgenic mouse by conditionally overexpressing the Notch1 intracellular domain (N1ICD) in the reproductive tract driven by a progesterone receptor (Pgr) -Cre. We show that the overexpression of N1ICD in the uterus results in complete infertility as a consequence of multiple developmental and physiological defects, including the absence of uterine glands and dysregulation of progesterone and estrogen signaling by a Recombination Signal Binding Protein Jκ-dependent signaling mechanism. We further show that the inhibition of progesterone signaling is caused by hypermethylation of its receptor Pgr by Notch1 overexpression through the transcription factor PU.1 and DNA methyltransferase 3b (Dnmt3b). We have generated a mouse model to study the consequence of increased Notch signaling in female reproduction and provide the first evidence, to our knowledge, that Notch signaling can regulate epigenetic modification of the Pgr. mouse uterus | Notch1 | Pgr | methylation | infertility

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“…P 4 signaling inhibits the estrogen signaling pathways in the uterus (Hsueh et al 1975) and this inhibitory relationship involving both hormone pathways orchestrate the regulatory mechanisms required for endometrial receptivity and embryo implantation. Amongst the regulated transcripts in the mid-secretory endometrium from women with mifepristone administration we found several genes involved in the P 4 signaling axis including modulators and effectors with down regulation of NCOA2 (SRC-2, (Mukherjee et al 2006, Jeong et al 2007), IHH (Matsumoto et al 2002, Takamoto et al 2002, ERRFI1 (MIG6, (Kim et al 2010)) PTCH1 (Lee et al 2006) and DKK1 ; and up-regulation of ESR1 (Curtis et al 1999), PRA (Conneely & Lydon 2000), FKBP5 (Tranguch et al 2005), FOXO1A (Kim et al 2005), KLF9 (Simmen et al 2004) and PTGS1 (Wang et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium

et al. 2016

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Progesterone regulates uterine function during the luteal phase and is essential for the acquisition of endometrial receptivity. The objective of the present study was to identify endometrial transcripts whose expression is altered during the window of implantation after the administration of 200 mg of the antiprogestin mifepristone, 48 h after the LH peak (LHC2, LHC0ZLH peak), and to determine the relationship of these transcripts with those regulated during the acquisition of receptivity. Endometrial samples were obtained in LHC7 from seven women of proven fertility, each one contributing with one cycle treated with placebo and another with mifepristone. Additionally, endometrial samples were obtained in LHC2 and LHC7 during a single untreated spontaneous cycle from seven normal fertile women as a reference. DNA microarrays were used to identify transcripts significantly regulated (defined as R2.0-fold change with false discovery rate below 1% using t-test) with the administration of mifepristone vs placebo, or during the transition from pre-receptive to receptive (LHC2 vs LHC7). Approximately 2000 transcripts were significantly regulated in both comparisons (mifepristone vs placebo and LHC2 vs LHC7), but only 777 of them were coincident and displayed opposite regulation except for 25. The mRNA level for eight selected genes regulated by mifepristone was confirmed by real-time RT-PCR. We conclude that not all changes in endometrial transcript levels occurring in the transition from LHC2 to LHC7 seem to be regulated by the progesterone receptor and w37% of the genes whose transcript levels changed by effect of mifepristone could be associated with the acquisition of receptivity.

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Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus

Cited by 252 publications

References 26 publications

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

Uterine epithelial estrogen receptor α is dispensable for proliferation but essential for complete biological and biochemical responses

Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases progesterone receptor by hypermethylation and leads to infertility

Effect of single post-ovulatory administration of mifepristone (RU486) on transcript profile during the receptive period in human endometrium

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