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

Significance Although many studies have yielded tremendous insights into the roles of TGF-β superfamily signaling pathways in physiological and pathophysiological processes, the in vivo roles of TGF-β signaling pathways in many aspects of reproduction remain largely unknown. To address these functions in females, we conditionally deleted the TGF-β type 1 receptor (activin receptor-like kinase 5, ALK5) and demonstrated that absence of TGF-β signaling through ALK5 in the uterus leads to striking abnormalities at different stages of pregnancy, including delayed implantation, disorganization of the trophoblast cells, significantly fewer uterine natural killer cells, and defects in spiral artery remodeling. Our findings provide a mouse model to investigate TGF-β signaling in reproduction and pave the way toward a better understanding of the pathogenesis of pregnancy-related complications in women. 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.