Uterine ALK3 is essential during the window of implantation

Proc Natl Acad Sci U S A. 2016 Jan 19;113(3):E387-95. doi: 10.1073/pnas.1523758113. Epub 2015 Dec 31.


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.

Keywords: BMP signaling pathway; endometrium; implantation failure; infertility; progesterone receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastocyst / drug effects
  • Blastocyst / metabolism
  • Bone Morphogenetic Protein Receptors, Type I / deficiency
  • Bone Morphogenetic Protein Receptors, Type I / metabolism*
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / metabolism
  • Decidua / drug effects
  • Decidua / metabolism
  • Embryo Implantation* / drug effects
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Estradiol / pharmacology
  • Female
  • Gene Deletion
  • Gene Expression Profiling
  • Infertility, Female / metabolism
  • Kruppel-Like Transcription Factors
  • Mice, Knockout
  • Models, Biological
  • Oligonucleotide Array Sequence Analysis
  • Ovary / drug effects
  • Ovary / physiology
  • Ovary / transplantation
  • Pregnancy
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Smad4 Protein / metabolism
  • Transcription Factors / metabolism
  • Uterus / drug effects
  • Uterus / metabolism*
  • Uterus / ultrastructure


  • DNA-Binding Proteins
  • Klf15 protein, mouse
  • Kruppel-Like Transcription Factors
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Smad4 Protein
  • Transcription Factors
  • Estradiol
  • Bmpr1a protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I