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Title: Krüppel-like factor 9 regulates cell proliferation and compartmental expression of estrogen and progesterone receptors in the mouse uterine endometrium

Author
item VELARDE, MICHAEL
item SIMMEN, FRANK
item SIMMEN, ROSALIA

Submitted to: Society for the Study of Reproduction Annual Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 4/15/2007
Publication Date: 7/1/2007
Citation: Velarde, M.C., Simmen, F.A., Simmen, R.C. 2007. Krüppel-like factor 9 regulates cell proliferation and compartmental expression of estrogen and progesterone receptors in the mouse uterine endometrium [abstract]. Biology of Reproduction. 2007 Special Issue:182.

Interpretive Summary: Estrogen and progesterone are steroid hormones that control the development of the uterus during the menstrual cycle and pregnancy. Here, we demonstrated the association of the gene responsible for the production of the KLF9 protein, which is thought to regulate the response of the uterus to estrogen and progesterone. Hence, our results provide important insights into the molecular signals during the development of the uterus that are required for normal menstrual cycle and successful pregnancy.

Technical Abstract: The uterine endometrium undergoes dynamic changes in proliferation and differentiation in response to estrogen (E) and progesterone (P) during the estrous cycle and pregnancy. E and P exert their functions through their respective nuclear receptors, estrogen receptor (ESR) and progesterone receptor (PGR), which interact with specific nuclear proteins to influence transcription. Our laboratory has identified Krüppel-like factor 9 (KLF9), a member of specificity protein (SP)/KLF family of transcription factors as a PGR-interacting protein that affects PGR transcriptional activity. Female mice null for the Klf9 gene have fewer numbers of successfully implanting embryos and decreased litter size, due partly to delayed onset of proliferation in uterine luminal epithelium (LE), resulting in asynchronous development between the embryo and the uterus. We hypothesize that the delayed initiation of endometrial cell proliferation in Klf9-knockout (KO) mice may be due to reduced uterine sensitivity to E and P mediated by KLF9. To address this, we compared endometrial cell proliferation in ovariectomized wild type (WT) and KO mice treated with E or P+EP following a regimen that mimicked the hormonal milieu of the uterine endometrium at early pregnancy. Endometrial cell proliferation was evaluated by immunostaining for Proliferating Cell Nuclear Antigen (PCNA). Acute E treatment (18h) increased PCNA immunoreactivity in endometrial LE, stroma (ST), and glandular epithelium (GE) in WT but not KO mice. Transcript levels of the proliferation-associated genes insulin-like growth factor I (Igf1) and CCAAT/enhancer binding protein, beta (Cebpb), measured by quantitative RT-PCR, were similar in uteri of WT and KO mice after acute E treatment. Chronic E treatment (32h) resulted in comparable PCNA immunoreactivity among cell types in both WT and KO mice. Proliferation status of LE, GE, and ST did not differ as a function of genotype with P+EP-treatment. Since ESR and PGR expression dictate cellular responsiveness to E and P, we determined if KLF9 influenced expression levels of ESR-' (ESR1) and PGR in LE, ST, and GE by immunohistochemistry. The absence of KLF9 in ST cells of KO mice resulted in subsequent loss of: (a) P+EP-mediated increase in LE cell ESR1 expression; (b) E-inhibition of LE cell PGR expression; and (c) P-mediated reversal of E-inhibition of LE cell PGR expression, relative to WT counterparts. Moreover, P+EP-induced increase in PGR-positive ST cells was higher in WT than in KO mice. Given that LE cells lack endogenous KLF9, results suggest that the timely proliferation of LE, which is requisite for its subsequent differentiation and receptivity to embryo implantation, is regulated by E/ESR1-mediated signaling from ST to LE, possibly via an ST-derived factor(s). Thus, KLF9 is an essential mediator of E and P action in the uterus via its distinct regulation of ESR1 and PGR expression levels in specific cell types. We suggest that ST expression of KLF9 is critical for communication between uterine LE and ST required for successful embryo implantation and pregnancy.