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Mol Endocrinol. 2015 Dec;29(12):1684-93. doi: 10.1210/me.2015-1048. Epub 2015 Oct 20.

Uterine Activin-Like Kinase 4 Regulates Trophoblast Development During Mouse Placentation.

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Departments of Pathology and Immunology (J.P., P.T.F., D.M., M.M.M.), Molecular and Human Genetics (J.P., P.T.F., M.M.M.), Molecular and Cellular Biology (M.M.M.), and Pharmacology (M.M.M.), Centers for Reproductive Medicine (M.M.M.) and Drug Discovery (P.T.F., D.M., M.M.M.), Baylor College of Medicine, Houston, Texas 77030; Department of Pathology (C.C.), New York University School of Medicine, New York, New York 10016; and Departments of Pathology (G.H.S.) and Otolaryngology/Head and Neck Surgery (G.H.S.), Columbia University College of Physicians and Surgeons, New York, New York 10032.


The placenta is the first organ to develop after fertilization. It forms an interface between the maternal uterus and growing fetus to allow nutrient uptake, waste elimination, and gas exchange for a successful pregnancy in both mice and humans. In the past 2 decades, in vivo and in vitro approaches have been used to show that several members of the TGF-β superfamily regulate embryo implantation and placental development. Nodal, a TGF-β superfamily ligand, is essential for mesendoderm formation and left-right axis patterning during embryogenesis, and Nodal null mutants exhibit abnormal placental organization with expansion of trophoblast giant cells and a decrease of spongiotrophoblast and labyrinth. To better understand the importance of Nodal signaling in the uterus, we established a mouse model to conditionally ablate activin-like kinase 4 (ALK4; the Nodal type 1 receptor) using Cre recombinase driven by the progesterone receptor promoter sequences (Pgr-Cre). Alk4 conditional knockout females are subfertile due to placental abnormalities and fetal loss in pregnancy, with a placental disorganization phenotype similar to what is observed in Nodal null mice. Thus, Nodal likely functions as an indirect regulator of placental development by binding to type 1 and type 2 receptors on maternal decidual cells to stimulate expression of unknown regulators of placental development. Our findings not only describe the generation of a mouse model that enables study of Nodal signaling in placentation but also provides insights into the pathogenesis of pregnancy complications in humans, including spontaneous abortion, preeclampsia, intrauterine growth restriction, and preterm birth.

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