Uterine activin receptor-like kinase 5 is crucial for blastocyst implantation and placental development

Proc Natl Acad Sci U S A. 2015 Sep 8;112(36):E5098-107. doi: 10.1073/pnas.1514498112. Epub 2015 Aug 24.


Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin receptor-like kinase 5 (ALK5) is the major type 1 receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine-cytokine receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction.

Keywords: TGF-β signaling; female reproduction; trophoblast cells; uNK; uterine luminal epithelium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Decidua / metabolism
  • Embryo Implantation / genetics*
  • Female
  • Fertility / genetics
  • Fluorescent Antibody Technique
  • Gene Expression Profiling*
  • Killer Cells, Natural / metabolism
  • Male
  • Mice, Knockout
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Placentation / genetics*
  • Pregnancy
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Trophoblasts / metabolism
  • Uterus / blood supply
  • Uterus / metabolism
  • Vascular Remodeling / genetics


  • Receptors, Transforming Growth Factor beta
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse