title: Uterine ALK3 is essential during the window of implantation.
abstract: The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3(flox) (/flox)-Pgr-cre-positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Diana
authors.initials: D
authors.lastname: Monsivais
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Caterina
authors.initials: C
authors.lastname: Clementi
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Jia
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Mary M
authors.initials: MM
authors.lastname: Titus
authors.affiliation: Electron Microscopy Laboratory, Texas Children's Hospital, Houston, TX 77030;
authors.forename: James P
authors.initials: JP
authors.lastname: Barrish
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030;
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
authors.affiliation: National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030; Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030 mmatzuk@bcm.edu.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Matzuk
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000187:drug effects / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D003656:Decidua / Q000187:drug effects / Q000378:metabolism; D010064:Embryo Implantation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D007247:Infertility, Female / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D018345:Mice, Knockout; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D010053:Ovary / Q000187:drug effects / Q000502:physiology / Q000637:transplantation; D011247:Pregnancy; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051901:Smad4 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D004268:DNA-Binding Proteins; C467418:Klf15 protein, mouse; D051741:Kruppel-Like Transcription Factors; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D051901:Smad4 Protein; D014157:Transcription Factors; D004958:Estradiol; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: BMP signaling pathway; endometrium; implantation failure; infertility; progesterone receptor