Estrogen-induced transcription factor EGR1 regulates c-Kit transcription in the mouse uterus to maintain uterine receptivity for embryo implantation

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>Early growth response 1 (Egr1) is a key transcription factor that mediates the action of estrogen (E<SUB>2</SUB>) to establish uterine receptivity for embryo implantation. However, few direct target genes of EGR1 have been identified in the uterus. Here, we demonstrated that E<SUB>2</SUB> induced EGR1-regulated transcription of c-Kit, which plays a crucial role in cell fate decisions. Spatiotemporal expression of c-Kit followed that of EGR1 in uteri of ovariectomized mice at various time points after E<SUB>2</SUB> treatment. E<SUB>2</SUB> activated ERK1/2 and p38 to induce EGR1, which then activated c-Kit expression in the uterus. EGR1 transfection produced rapid and transient induction of c-KIT in a time- and dose-dependent manner. Furthermore, luciferase assays to measure c-Kit promoter activity confirmed that a functional EGR1 binding site(s) (EBS) was located within −1 kb of the c-Kit promoter. Site-directed mutagenesis and chromatin immunoprecipitation-PCR for three putative EBS within −1 kb demonstrated that the EBS at -818/-805 was critical for EGR1-dependent c-Kit transcription. c-Kit expression was significantly increased in the uterus on day 4 and administration of Masitinib, a c-Kit inhibitor, effectively interfered with embryo implantation. Collectively, our results showed that estrogen induces transcription factor EGR1 to regulate c-Kit transcription for uterine receptivity for embryo implantation in the mouse uterus.</P> <P><B>Highlights</B></P> <P> <UL> <LI> c-Kit expression was significantly reduced in uteri of Egr1 (−/−) mice. </LI> <LI> Spatiotemporal expression patterns of c-Kit coincided with those of Egr1 in the uterus after E<SUB>2</SUB> treatment. </LI> <LI> E<SUB>2</SUB>-ER-dependent activation of the ERK1/2 and p38 MAPK-EGR1 pathway regulated c-Kit induction in the uterus. </LI> <LI> The EBS at −818/-805 was critical for EGR1-dependent activation of c-Kit transcription. </LI> <LI> c-Kit expression was significantly increased in mouse uteri receptive for embryo implantation. </LI> </UL> </P>