title: Mst1 and mst2 are essential regulators of trophoblast differentiation and placenta morphogenesis.
abstract: The placenta is essential for survival and growth of the fetus because it promotes the delivery of nutrients and oxygen from the maternal circulation as well as fetal waste disposal. Mst1 and Mst2 (Mst1/2), key components of the mammalian hpo/Mst signaling pathway, encode two highly conserved Ser/Thr kinases and play important roles in the prevention of tumorigenesis and autoimmunity, control of T cell development and trafficking, and embryonic development. However, their functions in placental development are not fully understood, and the underlying cellular and molecular mechanisms remain elusive. Here, we investigated the functions of Mst1/2 in mouse placental development using both conventional and conditional (endothelial) Mst1/2 double knockout mice. We found that the number of trophoblast giant cells dramatically increased while spongiotrophoblast cells almost completely disappeared in Mst1/2 deficient placentas. We showed that Mst1/2 deficiency down regulated the expression of Mash2, which is required for suppressing the differentiation of trophoblast giant cells. Furthermore, we demonstrated that endothelial-specific deletion of Mst1/2 led to impaired placental labyrinthine vasculature and embryonic lethality at E11.5, but neither affected vasculature in yolk sac and embryo proper nor endocardium development. Collectively, our findings suggest that Mst1/2 regulate placental development by control of trophoblast cell differentiation and labyrinthine vasculature at midgestation and Mst1/2 control labyrinth morphogenesis in trophoblast- and fetal endothelial-dependent manners. Thus, our studies have defined novel roles of Mst1/2 in mouse placental development.
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xingrong
authors.initials: X
authors.lastname: Du
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Donghua
authors.initials: D
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Ling V
authors.initials: LV
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China; Howard Hughes Medical Institute, Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Kejing
authors.initials: K
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Wufan
authors.initials: W
authors.lastname: Tao
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D010920:Placenta / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D010929:Placentation; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D014327:Trophoblasts / Q000166:cytology* / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; C489311:Ascl2 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse