Early growth response 1 (Egr1) belongs to the Egr family of zinc finger transcription factors (Egr1 to Egr4) that regulates cell growth, differentiation, and apoptosis. Egr1(-/-) female mice are infertile due to anovulation resulting from luteinizing hormone β subunit (LHβ) deficiency. While it is clear that Egr1 is critical for LHβ transcription in the pituitary gland, function of Egr1 in uterus still remain unexplored. Uteri on various experimental conditions or days of pregnancy were collected for mRNA microarrays, realtime-RT-PCR, Western blotting, and histological analyses for immunofluorescence and BrdU staining. Egr1 and other Egr family members, Egr2 and Egr3 are highly expressed in the uterus on day 4 of pregnancy (Day 4). While ovulation, fertilization and embryo development normally occur in Egr1(-/-) mice treated with a superovulation regime to rescue LH deficiency, embryo implantation was completely failed. In addition to implantation failure, oviductal transport of embryos is also impaired in these mice. 17/24 Egr1(-/-) mice (71%) retained blastocysts in the oviduct as well as in the uterus of Egr1(-/-) mice on Day 4 whereas all Egr1(+/+) mice have them in the uterus. While serum levels of E2 and P4 in Egr1(-/-) mice on Day 4 were comparable to those of wildtypes, expression of E2 responsive genes which are expressed in luminal epithelium, such as Mucin 1 and lactoferrin, is aberrantly increased in Egr1(-/-) mice with embryos in the oviduct on Day 4. In contrast, P4 responsive genes such as Hoxa10 and amphiregulin are normally expressed in these mice. Collectively, these data suggest that Egr1 deficiency in the oviduct and uterus leads to estrogen hypersensitivity. BrdU incorporation experiments provided evidence that epithelial cells undergo hyperproliferation in Egr1(-/-) mice. This is consistent with microarray data that several key factors for cell cycle progression such as cyclin Ds and E2F1 are overexpressed in these mice. Furthermore, in the uteri of Egr1(-/-) mice treated with E2+P4, stromal cell proliferation is severely impaired and epithelial cells persistently proliferating. With respect to decidualization, Egr1 as well as Egr2 and Egr3 are induced immediately after decidualization stimuli were given. Although the responses were relatively less than those of wildtype mice, decidualization does occur in Egr1(-/-) mice. Relatively compromised decidualization responses seems to result from functional compensation of Egr2 and Egr3 in Egr1(-/-) deficient uteri. Collectively, our results show that Egr1 is a critical transcription factor to fine-tune estrogen responses via regulation of a spectrum of genes for embryo implantation in the uterus.

• Hye-Ryun Kim(Department of Biomedical Science, CHA University, Fertility Center of CHA Gangnam Medical Center, CHA University)
• Yeon Sun Kim(Department of Biomedical Science, CHA University)
• Jung Ah Yoon(Department of Biomedical Science, CHA University, Fertility Center of CHA Gangnam Medical Center, CHA University)
• Haengseok Song(Department of Biomedical Science, CHA University, Fertility Center of CHA Gangnam Medical Center, CHA University)