Deletion of Stk40 impairs definitive erythropoiesis in the mouse fetal liver

Cell Death Dis. 2017 Mar 30;8(3):e2722. doi: 10.1038/cddis.2017.148.

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.

MeSH terms

  • Animals
  • Erythroblasts / metabolism*
  • Erythropoiesis / physiology*
  • Fetus / embryology*
  • Gene Deletion
  • Liver / embryology*
  • Megakaryocyte Progenitor Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*

Substances

  • Protein Serine-Threonine Kinases
  • Stk40 protein, mouse