Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation

Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 01/2012; 109(4):1145-50. DOI: 10.1073/pnas.1118411109
Source: PubMed


A blastocyst will implant only when the uterus becomes receptive. Following attachment, luminal epithelial cells undergo degeneration at the site of the blastocyst. Although many genes critical for uterine receptivity are primarily regulated by ovarian hormones, Kruppel-like factor 5 (KLF5), a zinc finger-containing transcription factor, is persistently expressed in epithelial cells independently of ovarian hormones. Loss of uterine Klf5 causes female infertility due to defective implantation. Cox2 is normally expressed in the luminal epithelium and stroma at the site of blastocyst attachment, but luminal epithelial COX2 expression is absent with loss of Klf5. This is associated with the retention of the epithelium around the implantation chamber with arrested embryonic growth. These results suggest that Klf5 is indispensable for normal implantation.

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Available from: Huirong Xie, Feb 19, 2014
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    • "Several KLFs have been directly linked to the regulation of inflammatory signaling, defects of which may contribute to uterine pathology. In particular, uterine-specific Klf5-null mice are infertile due to aberrant expression of the prostaglandin synthesis gene Ptgs2, resulting in the enhanced expression of COX2 (Sun et al. 2012). Similarly, KLF11, the attenuated expression of which is linked to uterine leiomyoma, has been reported to inhibit prostaglandin E 2 synthesis by transcriptionally silencing the promoter of the gene encoding phospholipase A 2a , the key enzyme for prostaglandin biosynthesis (Buttar et al. 2010). "
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    ABSTRACT: Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.
    Journal of Molecular Endocrinology 02/2015; 54(2). DOI:10.1530/JME-14-0310 · 3.08 Impact Factor
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    • "As shown in Figure 3C and Supplementary information, Figure S4, and delineated in Figure 3D, the implanting blastocysts in the Rbpjd/d uteri used an abnormal epithelial fold as the implantation chamber. The embryonic disorientation was further demonstrated by the expression of COX2, an implantation marker that is typically localized around the antimesometrial side of the normal implantation chamber34,35, which is abnormally located along with the deflected embryo orientation in Rbpjd/d mice (Figure 3C). "
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    ABSTRACT: Coordinated uterine-embryonic axis formation and decidual remodeling are hallmarks of mammalian post-implantation embryo development. Embryonic-uterine orientation is determined at initial implantation and synchronized with decidual development. However, the molecular mechanisms controlling these events remain elusive despite its discovery a long time ago. In the present study, we found that uterine-specific deletion of Rbpj, the nuclear transducer of Notch signaling, resulted in abnormal embryonic-uterine orientation and decidual patterning at post-implantation stages, leading to substantial embryo loss. We further revealed that prior to embryo attachment, Rbpj confers on-time uterine lumen shape transformation via physically interacting with uterine estrogen receptor (ERα) in a Notch pathway-independent manner, which is essential for the initial establishment of embryo orientation in alignment with uterine axis. While at post-implantation stages, Rbpj directly regulates the expression of uterine matrix metalloproteinase in a Notch pathway-dependent manner, which is required for normal post-implantation decidual remodeling. These results demonstrate that uterine Rbpj is essential for normal embryo development via instructing the initial embryonic-uterine orientation and ensuring normal decidual patterning in a stage-specific manner. Our data also substantiate the concept that normal mammalian embryonic-uterine orientation requires proper guidance from developmentally controlled uterine signaling.Cell Research advance online publication 27 June 2014; doi:10.1038/cr.2014.82.
    Cell Research 06/2014; DOI:10.1038/cr.2014.82 · 12.41 Impact Factor
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    • "stem cells, KLF5 plays an important role in self-renewal and maintenance of pluripotency (Nandan and Yang, 2009). During mouse embryogenesis, tissue specific deletion of Klf5 demonstrates its requirement for implantation (Sun et al., 2012), adipocyte differentiation (Oishi et al., 2005), bladder urothelial maturation (Bell et al., 2011), terminal maturation of lung epithelial cells (Wan et al., 2008), and postnatal-development of the eyelid and cornea (Kenchegowda et al., 2011). Klf5 is highly expressed throughout development in the gastrointestinal epithelium (Dong and Chen, 2009). "
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    ABSTRACT: Kruppel-like factor 5 (Klf5) is a transcription factor expressed by embryonic endodermal progenitors that form the lining of the gastrointestinal tract. A Klf5floxed allele was efficiently deleted from the intestinal epithelium by a Cre transgene under control of the Shh promoter resulting in the inhibition of villus morphogenesis and epithelial differentiation. Although proliferation of the intestinal epithelium was maintained, the expression of Elf3, Pparγ, Atoh1, Ascl2, Neurog3, Hnf4α, Cdx1,and other genes associated with epithelial cell differentiation was inhibited in the Klf5-deficient intestines. At E18.5, Klf5(Δ/Δ) fetuses lacked the apical brush border characteristic of enterocytes, and a loss of goblet and enteroendocrine cells was observed. The failure to form villi was not attributable to the absence of HH or PDGF signaling, known mediators of this developmental process. Klf5-deletion blocked the decrease in FoxA1 and Sox9 expression that accompanies normal villus morphogenesis. KLF5 directly inhibited activity of the FoxA1 promoter, and in turn FOXA1 inhibited Elf3 gene expression in vitro, linking the observed loss of Elf3 with the persistent expression of FoxA1observed in Klf5-deficient mice. Genetic network analysis identified KLF5 as a key transcription factor regulating intestinal cell differentiation and cell adhesion. These studies indicate a novel requirement for KLF5 to initiate morphogenesis of the early endoderm into a compartmentalized intestinal epithelium comprised of villi and terminally differentiated cells.
    Developmental Biology 12/2012; 375(2). DOI:10.1016/j.ydbio.2012.12.010 · 3.55 Impact Factor
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