Uterine ALK3 is essential during the window of implantation (Oct 2015)

Uterine ALK3 is essential during the window of implantation
PNAS; vol.113 no.3, E387-E395; DOI: 10.1073
Diana Monsivaisa,b,1, Caterina Clementia,1,2, Jia Penga,3, Mary M. Titusa, James P. Barrishc, Chad J. Creightond,e, John P. Lydonb,f, Francesco J. DeMayog, and Martin M. Matzuka,b,e,f,h,i,j,4
Author(s) affiliation:
aDepartment of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
bCenter for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030;
cElectron Microscopy Laboratory, Texas Children’s Hospital, Houston, TX 77030;
dDepartment of Medicine, Baylor College of Medicine, Houston, TX 77030;
eDan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030;
fDepartment of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030;
gNational Institute of Environmental Health Sciences, Research Triangle Park, NC 27709;
hDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;
iDepartment of Pharmacology, Baylor College of Medicine, Houston, TX 77030;
jCenter for Drug Discovery, Baylor College of Medicine, Houston, TX 77030
1D.M. and C.C. contributed equally to this work.
2Present address: Celmatix Inc., New York, NY 10005.
3Present address: Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
4To whom correspondence should be addressed. Email: This email address is being protected from spambots. You need JavaScript enabled to view it..


Short description:
In the assisted reproductive technology (ART) clinic, pregnancy is defined by the rise of human chorionic gonadotropin upon embryo implantation. Achieving embryo implantation is a major roadblock to the success of ART; it is estimated that only 50% of transferred embryos implant in patients seeking ART, and that half of these embryos are subsequently lost. Thus, understanding the molecular pathways during the window of implantation will improve ART success. In this study, we conditionally deleted activin-like kinase 3 (ALK3) in mice and demonstrate that bone morphogenetic protein (BMP) signaling via ALK3 defines uterine receptivity. This mouse model will be a valuable research tool for studying implantation failure in women, and the results herein will contribute to our knowledge regarding female infertility.
Link to the journal


Abstract taken from PubMed

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.
Link to the paper on PubMed


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