title: Protein phosphatase 2A catalytic subunit α (PP2Acα) maintains survival of committed erythroid cells in fetal liver erythropoiesis through the STAT5 pathway.
abstract: Suppression of programmed cell death is critical for the final maturation of red blood cells and depends largely on the anti-apoptotic effects of EpoR-STAT5-Bcl-x(L) signaling. As the major eukaryotic serine/threonine phosphatase, protein phosphatase 2A (PP2A) regulates multiple cellular processes, including apoptosis. However, whether PP2A plays a role in preventing erythroid cells from undergoing apoptosis remains to be elucidated. We conditionally inactivated the catalytic subunit α of PP2A (PP2Acα), which is the predominant form of PP2Ac, during early embryonic hematopoiesis. Loss of PP2Acα in hematopoietic cells perturbed definitive erythropoiesis characterized by fetal liver atrophy, reduced Ter119(+) cell number, abnormal expression patterns of molecular markers, less colony formation, and a reduction in definitive globin expression. Levels of erythropoiesis-promoting cytokines and initial seeding with hematopoietic progenitors remained unchanged in PP2Acα(TKO) fetal livers. We noted impaired expansion of the fetal erythroid compartment, which was associated with increased apoptosis of committed erythroid cells. Mechanistically, PP2Acα depletion markedly reduced Tyr(694) phosphorylation of STAT5 and expression of Bcl-x(L). Unexpectedly, PP2Acα-deficient embryos did not manifest any early embryonic vascular defects. Collectively, these data provide direct loss-of-function evidence demonstrating the importance of PP2Acα for the survival of committed erythroid cells during fetal liver erythropoiesis.
authors.affiliation: Key Laboratory of Model Animal for Disease Study of Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.forename: Pengyu
authors.initials: P
authors.lastname: Gu
authors.forename: Xuan
authors.initials: X
authors.lastname: Jiang
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.forename: Chaojun
authors.initials: C
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D004622:Embryo, Mammalian; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050799:STAT5 Transcription Factor; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C