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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-? 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 ? (TGF-?) 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.

SUBMITTER: Monsivais D

PROVIDER: S-EPMC4725477 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Uterine ALK3 is essential during the window of implantation.

Monsivais Diana D Clementi Caterina C Peng Jia J Titus Mary M MM Barrish James P JP Creighton Chad J CJ Lydon John P JP DeMayo Francesco J FJ Matzuk Martin M MM

Proceedings of the National Academy of Sciences of the United States of America 20151231 3

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 postimplantatio ...[more]

PMID: 26721398

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Project description:Purpose: Extracellular vescicles (EVs) of uterine origin have recently been identified, but they are not comprised by current diagnostics on endometrial receptivity. In order to test the possibility to use EVs as biomarker reservoirs for non-invasive monitoring of the endometrial status, we defined two experimental designs: in step a) we aimed at assessing the concordance between the transcriptome of endometrial tissue and uterine fluid-derived EVs (UF-EVs); in step b) we aimed at unraveling the transcriptomic profile of UF-EVs released during the receptive phase and associated with successful implantation Methods: RNAseq analysis was performed on total RNA isolated from a) endometrial biopsies and UF-EVs concomitantly collected from regularly cycling women; b) UF-EVs collected in the pre-receptive (LH+2) versus the receptive (LH+7) phase of provenly fertile women and in the receptive phase (LH+7) of women undergoing assisted reproduction and transfer of an euploid blastocyst. In the latter group, the outcomes of the following embryo transfer attempt were recorded, in order to compare the transcriptomic profile of women with successful versus failed implantation. Differential Gene Expression (DGE) and Gene Set Enrichment (GSEA) analyses were performed. Results: In the first experimental design, a highly significant correlation was found between the transcriptional profiles of endometrial tissue biopsies and corresponding UF-EVs (r=0.71 p<0.001; ρ=0.65 p<0.001). In the second experimental design, using a large group of 73 samples, 16,777 genes were overall found to be expressed in UF-EVs. Of these, DGE analysis showed that 942 were up-regulated and 1,305 down-regulated during the receptive phase in women with proven fertility and 97 were up-regulated and 64 down-regulated during the receptive phase of women achieving successful implantation versus women failing to achieve pregnancy in the subsequent cycle. 41 genes had a statistically significant different expression in both comparisons. We additionally tested wether transcripts used by current endometrial receptivity tests based on endometrial biopsies (Endometrial Receptivity Assay, ERA test) could also be detected in UF-EVs: out of 238 ERA test gene data-set, GSEA highlighted 219 genes with similar transcriptional profile in UF-EVs. We then performed another comparison adding the list of genes consisting of the ‘metasignature’ transcriptome derived from the published meta-analysis of endometrial receptivity associated transcripts, comprising 57 genes. This last intersection identified 38 genes expressed in UF-EVs that i) show differential expression with the same transcriptional profile (same trends) in both EVs and ERA test assay; ii) belong to the leading edge of genes with the most significant enrichment score in our analysis; iii) are identified as receptivity-associated genes by the current meta-analysis on endometrial transcriptome. Conclusions: This is the first study showing the capacity of UF-EVs to reflect the endometrial tissue transcriptional status and to establish a signature of genes expressed in UF-EVs that might serve as putative biomarkers for non-invasive endometrial receptivity tests.

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Uterine ALK3 is essential during the window of implantation.

Publications

Uterine ALK3 is essential during the window of implantation.

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