Depletion of Ppp6c in hematopoietic and vascular endothelial cells causes embryonic lethality and decreased hematopoietic potential

• Published in: Experimental hematology 2024-05, Vol.133, p.104205, Article 104205
• Main Authors: Kondo, Ayumi, Tanaka, Hirokazu, Rai, Shinya, Shima, Hiroshi, Matsumura, Itaru, Watanabe, Toshio
• Format: Article
• Language: English
• Subjects: Animals; Embryo Loss - genetics; Embryo Loss - pathology; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Hematopoiesis; Hematopoietic Stem Cells - metabolism; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Knockout; Phosphoprotein Phosphatases - deficiency; Phosphoprotein Phosphatases - genetics; Phosphoprotein Phosphatases - metabolism
• ISSN: 0301-472X; 1873-2399; 1873-2399
• DOI: 10.1016/j.exphem.2024.104205

•PP6 is indispensable for embryonic hematopoiesis.•Ppp6c depletion in hematopoietic and endothelial cells causes embryonic lethality.•PP6 is necessary for the hematopoietic potential of embryonic LSK cells. Protein phosphatase 6 (PP6) is a serine/threonine (Ser/Thr) protein phosphatase, and its catalytic subunit is Ppp6c. PP6 forms the PP2A subfamily with PP2A and PP4. The diverse phenotypes observed following small interfering RNA (siRNA)-based knockdown of Ppp6c in cultured mammalian cells suggest that PP6 plays roles in cell growth and DNA repair. There is also evidence that PP6 regulates nuclear factor kappa B (NF-κB) signaling and mitogen-activated protein kinases and inactivates transforming growth factor-β-activated kinase 1 (TAK1). Loss of Ppp6c causes several abnormalities, including those of T cell and regulatory T cell function, neurogenesis, oogenesis, and spermatogenesis. PP2A has been reported to play an important role in erythropoiesis. However, the roles of PP6 in other hematopoietic cells have not been investigated. We generated Ppp6cfl/fl;Tie2-Cre (Ppp6cTKO) mice, in which Ppp6c was specifically deleted in hematopoietic and vascular endothelial cells. Ppp6cTKO mice displayed embryonic lethality. Ppp6c deficiency increased the number of dead cells and decreased the percentages of erythroid and monocytic cells during fetal hematopoiesis. By contrast, the number of Lin−Sca-1+c-Kit+ cells, which give rise to all hematopoietic cells, was slightly increased, but their colony-forming cell activity was markedly decreased. Ppp6c deficiency also increased phosphorylation of extracellular signal-regulated kinase 1/2 and c-Jun amino (N)-terminal kinase in fetal liver hematopoietic cells.