title: Deletion of Stk40 impairs definitive erythropoiesis in the mouse fetal liver.
abstract: The serine threonine kinase Stk40 has been shown to involve in mouse embryonic stem cell differentiation, pulmonary maturation and adipocyte differentiation. Here we report that targeted deletion of Stk40 leads to fetal liver hypoplasia and anemia in the mouse embryo. The reduction of erythrocytes in the fetal liver is accompanied by increased apoptosis and compromised erythroid maturation. Stk40-/-fetal liver cells have significantly reduced colony-forming units (CFUs) capable of erythroid differentiation, including burst forming unit-erythroid, CFU-erythroid (CFU-E), and CFU-granulocyte, erythrocyte, megakaryocyte and macrophage, but not CFU-granulocyte/macrophages. Purified Stk40-/-megakaryocyte-erythrocyte progenitors produce substantially fewer CFU-E colonies compared to control cells. Moreover, Stk40-/-fetal liver erythroblasts fail to form normal erythroblastic islands in association with wild type or Stk40-/-macrophages, indicating an intrinsic defect of Stk40-/-erythroblasts. Furthermore, the hematopoietic stem and progenitor cell pool is reduced in Stk40-/-fetal livers but still retains the multi-lineage reconstitution capacity. Finally, comparison of microarray data between wild type and Stk40-/-E14.5 fetal liver cells reveals a potential role of aberrantly activated TNF-α signaling in Stk40 depletion induced dyserythropoiesis with a concomitant increase in cleaved caspase-3 and decrease in Gata1 proteins. Altogether, the identification of Stk40 as a regulator for fetal erythroid maturation and survival provides new clues to the molecular regulation of erythropoiesis and related diseases.
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Hongyao
authors.initials: H
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Ke
authors.initials: K
authors.lastname: He
authors.affiliation: Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Science, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Zhuoqing
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Laixiang
authors.initials: L
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.|Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China.|Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.|Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Science, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D004900:Erythroblasts / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology*; D005333:Fetus / Q000196:embryology*; D017353:Gene Deletion; D008099:Liver / Q000196:embryology*; D055016:Megakaryocyte Progenitor Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017346:Protein Serine-Threonine Kinases; C547661:Stk40 protein, mouse